Heterocyclic alkyl naphthols

ABSTRACT

Aminoalkylnaphthols and esters thereof, useful as cardiotonic or antibacterial agents, are prepared from the corresponding RO-naphthalenealkylamines, certain of which are also useful as cardiotonic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending application Ser.No. 388,962, filed August 16, 1973 now U.S. Pat. No. 4,169,108, issuedSept. 25, 1979.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a series of aminoalkylsubstitutednaphthalenediols or naphthols useful as cardiotonic and/or antimicrobialagents and to intermediates for the preparation thereof.

2. Prior Art

The compounds disclosed in the following references are believed to bethe art most pertinent to the present invention. Bond et al., U.S. Pat.No. 3,463,808, patented Aug. 26, 1969 discloses a group of naphthalenederivatives of the formula ##STR1## wherein R¹ stands for hydrogen or analkyl, hydroxyalkyl, cycloalkyl, alkenyl or arylalkyl radical and ring Bbears a hydroxy or acyloxy substituent or it bears two alkoxysubstituents and wherein the naphthalene nucleus optionally bears one ormore additional substituents and the esters thereof and the saltsthereof. These compounds are stated to be β-adrenergic blocking agents.

Webb, et al. U.S. Pat. No. 3,131,214, patented Apr. 28, 1964 disclosesas insecticides a group of3-dimethylaminomethyl-4-methyl-1,8-di-substituted naphthalenes of theformula ##STR2## wherein R is hydrogen, lower alkyl or lower acyl.

Sus U.S. Pat. No. 3,046,117, patented July 24, 1962 discloses in mostpertinent part a group of 2(or 4)-hydroxy-1-naphthylmethylamines and2,7-dihydroxy-1-naphthylmethylamines as intermediates in the preparationof light-sensitive orthoquinone diazides used in the manufacture ofprinting plates.

Stephenson U.S. Pat. No. 3,215,732, patented Nov. 2, 1965 which relatesto a group of naphthalene derivatives stated to be of value in thetreatment or prophylaxis of coronary artery disease discloses in mostpertinent part[2-hydroxy-2-(6'-methoxy-2'-naphthyl)-ethyl]isopropylamine.

Horil et al., Chem. Pharm. Bull., 19, 1245-1256 (1971) discloses aschemical intermediates a group of mono- anddimethoxy-N,N-dimethylnaphthalenemethylamines.

Khorana, Indian J. Pharm., 23, 297 (1961); Chemical Abstracts, 57,15023d (1962) discloses in most pertinent part6-hydroxy-2-naphthaleneacetanilide.

S. V. Kessar, Tetrahedron Letters, 3245-3247 (1965) discloses as achemical intermediate 6-methoxy-1-naphthylethylamine.

Beaudet, et al., Bull. Ste. Chim. Biol. 34, 952-955 (1952) discloses7-methoxy-1-naphthylethylamine as a potential intermediate in thepreparation of the corresponding 7-hydroxy-compound. However,preparation of the latter was unsuccessful.

Dey et al., Arch. Pharm., 277, 359-374 (1939) discloses in mostpertinent part 2-methoxy and 2-hydroxy-1-naphthylmethylamine as chemicalintermediates.

King et al., J. Chem. Soc., 1307-1315 (1940) discloses in most pertinentpart 7-methoxy-α-piperidinomethyl-1-naphthalenemethanol which was testedand found inactive as an antiplasmodial agent.

Winstein et al., J. Org. Chem., 11, 150-156 (1946) discloses a methodfor the preparation of4-methoxy-α-(dibutylaminomethyl)-1-naphthalenemethanol.

A. Madinaveitia, Anal. Fis. Quim., 18, 66 (1920); Chemical Abstracts 16,92 (1922) discloses 1-aminoacetyl-4-methoxynaphthalene.

H. L. Holmes et al., JACS, 69, 2000-2003 (1947) discloses as a chemicalintermediate 6,7-dimethoxy-2-naphthamide.

W. H. Hartung et al., JACS, 57, 1091-1093 (1935) discloses 2-oximinopropionaphthone as a chemical intermediate.

Syntex Corporation, British Pat. No. 1,276,261, published June 1, 1972,discloses a group of substituted2-(5',7'-dimethoxy-2'-naphthyl)propionamides stated to be useful asanalgesic, anti-pyretic and anti-inflammatory agents.

3. Prior Publications

The following publications appeared subsequent to the invention claimedherein and less than one year prior to the filing date of parentapplication Ser. No. 388,962.

K. Y. Zee-Cheng et al., J. Heterocyclic Chem., 9, 805-811, (1972)discloses as chemical intermediates a group of naphthylethylamineshaving the formula ##STR3## wherein R₁ ═R₂ ═CH₃ and R═H, CH₃ or C₆ H₅CH₂

R₁ +R₂ =CH₂ and R═H.

Richardson-Merrell, Belgian Pat. No. 783,271, published Sept. 1, 1972,discloses as intermediates compounds having the formula ##STR4## whereininter alia Y is 1 to 6 carbon alkylene and R is 1 to 3 carbon alkoxy.However, the only disclosure in the reference relating toalkoxy-substituted compounds resides in reference to the previouslyknown 4-methoxy-α-methylnaphthalenemethylamine and6-methoxy-1-naphthylethylamine described by Dey et al. and Kessar etal., both cited hereinabove.

SUMMARY OF THE INVENTION

The present invention relates to a series of aminoalkyl-substituted2,3-naphthalenediols, 1,3-naphthalenediols, 1,5-naphthalenediols,2-naphthols and esters thereof having cardiotonic and/or antibacterialactivity.

The invention also provides a series of aminoalkylsubstituted6,7-dialkoxynaphthalenes, 6,8-dialkoxynaphthalenes,4,8-dialkoxynaphthalenes and 2-alkoxynaphthalenes useful asintermediates in the preparation of the corresponding naphthalenediolsand naphthols. Certain of these compounds are also useful as cardiotonicagents.

DETAILED DESCRIPTION OF THE INVENTION INCLUSIVE OF THE PREFERREDEMBODIMENTS

In one of its composition aspects, the invention sought to be patentedresides in the substituted 5(and 6)-aminoalkyl-A-2,3-naphthalenediolshaving Formula I hereinbelow: ##STR5## wherein the side chainrepresented by ##STR6## occupies either position 5 or position 6 of thenaphthalene nucleus; R and R₁ are independently hydrogen, lower-alkanoylor aroyl;

Q is hydrogen or methyl;

A is carbonyl, CHOH, a direct linkage or CR₅ R₆ where R₅ and R₆ areindependently hydrogen or methyl;

R₂ is hydrogen or methyl, provided that when A is a direct linkage, orwhen R₅ and/or R₆ are methyl, then R₂ is hydrogen;

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl, or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two loweralkyl substituents;

or an acid-addition salt thereof;

provided that when A is CR₅ R₆ and R₃ and R₄ are independently hydrogen,lower-alkyl, benzyl or aryl, then at least one of R and R₁ islower-alkanoyl or aroyl.

These compounds are useful as cardiotonic agents as described more fullyhereinbelow. Furthermore, the diols of Formula I (R=R₁ =H; A is C═O, adirect linkage or CR₅ R₆ as defined hereinabove) are also used toprepare the corresponding ester derivatives wherein at least one of Rand R₁ is lower-alkanoyl or aroyl while the other is hydrogen, orwherein both R and R₁ are lower-alkanoyl or aroyl. The compounds ofFormula I wherein A is carbonyl are also useful as intermediates in thepreparation of the corresponding alcohols having Formula I wherein A isCHOH.

Because of high cardiotonic activity, preferred embodiments of thepresent invention reside in the substituted6-aminoethyl-A-2,3-naphthalenediols having Formula I hereinabovewherein:

the side chain represented by ##STR7## occupies position 6 of thenaphthalene nucleus; R, R₁ and R₂ are hydrogen;

A is CR₅ R₆ where R₅ and R₆ are both hydrogen; and

NR₃ R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or anyof these having from one to two lower-alkyl substituents.

A particularly preferred species is6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol.

In another composition aspect the invention sought to be patentedresides in the substituted 5(and 6)-aminoalkyl-2,3-naphthalenediolshaving Formula II ##STR8## wherein the side chain represented by##STR9## occupies either position 5 or position 6 of the naphthalenenucleus; R and R₁ are independently hydrogen, lower-alkanoyl or aroyl;

Q is hydrogen or methyl;

R₂, R₇ and R₈ are independently hydrogen or methyl;

Z is hydrogen, hydroxy or methoxy; and

n is 1, 2 or 3;

or an acid-addition salt thereof.

These compounds are useful as cardiotonic agents. Certain species arealso useful as antibacterial agents. Moreover, the diols (Formula II,R═R₁ ═H) are useful as intermediates in the preparation of thecorresponding esters (Formula II, at least one of R and R₁ islower-alkanoyl or aroyl).

In yet another composition aspect the invention resides in thesubstituted 7(and 8)-aminoalkyl-1,3-naphthalenediols having Formula IIIhereinbelow: ##STR10## wherein the side chain represented by ##STR11##occupies either position 7 or position 8 of the naphthalene nucleus; Rand R₁ are independently hydrogen, lower-alkanoyl or aroyl;

R₅ and R₆ are independently hydrogen or methyl; and

R₃ and R₄ are independently hydrogen, lower-alkyl, aryl, or NR₃ R₄ ispyrrolidino, piperidino, hexamethyleneimino, morpholino or any of thesehaving from one to two lower-alkyl substituents;

or an acid-addition salt thereof.

These compounds are useful as cardiotonic agents. Certain species arealso useful as antibacterial agents. Moreover, the diols (Formula III,R═R₁ ═H) are useful as intermediates in the preparation of thecorresponding esters (Formula III; at least one of R and R₁ islower-alkanoyl or aroyl).

In still another composition aspect, the invention resides in thesubstituted 4-aminoalkyl-1,5-naphthalenediols having Formula IVhereinbelow ##STR12## wherein R and R₁ are independently hydrogen,lower-alkanoyl or aroyl;

A is carbonyl, CHOH or methylene;

R₂ is hydrogen or methyl, and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl, or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two loweralkyl substituents;

or an acid-addition salt thereof.

These compounds are useful as cardiotonic agents. Certain species arealso useful as antibacterial agents. Moreover, the diols of Formula IV(R═R₁ ═H) are useful as intermediates in the preparation of thecorresponding esters (Formula IV; at least one of R and R₁ is loweralkanoyl or aroyl). The ketones (Formula IV, A is carbonyl) are alsoused to prepare the corresponding alcohols (Formula IV, A is CHOH).

In a further composition aspect, the invention sought to be patentedresides in the substituted 6(and 7)-aminoalkyl-2-naphthols having, inthe free base form, the Formula V hereinbelow ##STR13## wherein the sidechain represented by ##STR14## occupies either position 6 or position 7of the naphthalene nucleus; R is hydrogen, lower-alkanoyl, or aroyl;

R₂, R₅ and R₆ are each hydrogen or methyl provided that when R₂ ismethyl, R₅ and R₆ are hydrogen;

R₃ and R₄ are hydrogen, lower-alkyl, benzyl, aryl or NR₃ R₄ ispyrrolidino, piperidino, hexamethyleneimino, morpholino or any of thesehaving from one to two lower-alkyl substituents;

or an acid-addition salt thereof.

These compounds are useful as cardiotonic agents. Because of highcardiotonic activity a preferred species of Formula V is6-(2-aminoethyl)-2-naphthol.

In another composition aspect the invention sought to be patentedresides in the compounds having Formula VI hereinbelow ##STR15## whereinthe side chain represented by ##STR16## occupies either position 1 orposition 2 of the naphthalene nucleus; R is lower-alkyl or benzyl; orboth R groups together constitute a methylene group bonded to bothoxygen atoms;

Q is hydrogen or methyl;

A is carbonyl, a direct linkage or CR₅ R₆ where R₅ and R₆ areindependently hydrogen or methyl;

R₂ is hydrogen or methyl, provided that when A is a direct linkage, orwhen R₅ and/or R₆ are methyl then R₂ is hydrogen, and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two loweralkyl substituents; provided that whenA is carbonyl and R₂ is hydrogen, then NR₃ R₄ is not amino, and when Ais methylene and R₂ is hydrogen, then NR₃ R₄ is not methylamino orbenzylamino;

or an acid-addition salt thereof.

These compounds are useful as cardiotonic agents and as intermediates inthe preparation of the compounds of this invention having Formula I (Ais C═O, a direct linkage or CR₅ R₆ as defined hereinabove). In addition,the amines of Formula VI wherein A is methylene, and Q, R₂ and R₃ arehydrogen are useful as intermediates in the preparation of the compoundsof Formula VII described hereinbelow. The amino ketones (Formula VI, Ais C═O) are also useful as intermediates in the preparation of theamines of Formula VI wherein A is methylene.

Because of high cardiotonic activity, preferred species of Formula VIare those wherein:

the side chain represented by ##STR17## occupies position 2 of thenaphthalene nucleus; R is lower-alkyl;

R₂ is hydrogen;

A is CR₅ R₆ where R₅ and R₆ are both hydrogen;

R₃, R₄ and NR₃ R₄ have the same significance indicated hereinabove.

Particularly preferred species areN-ethyl-6,7-dimethoxynaphthaleneethylamine,N,N-dimethyl-6,7-dimethoxynaphthaleneethylamine,1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]pyrrolidine, and1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]piperidine.

Another composition aspect of the invention resides in the compoundshaving Formula VII hereinbelow ##STR18## wherein the side chainrepresented by ##STR19## occupies either position 1 or position 2 of thenaphthalene nucleus; R is lower-alkyl or benzyl, or both R groupstogether constitute a methylene group bonded to both oxygen atoms;

Q is hydrogen or methyl;

R₂, R₇ and R₈ are independently hydrogen or methyl;

Z is hydrogen, hydroxy or methoxy; and

n is 1, 2 or 3;

or an acid-addition salt thereof.

These compounds are useful as intermediates in the preparation of thecorresponding diols of Formula II.

In another composition aspect, the invention resides in the compoundshaving Formula VIII hereinbelow ##STR20## wherein the side chainrepresented by ##STR21## occupies either position 1 or position 2 of thenaphthalene nucleus; R is lower alkyl;

R₅ and R₆ are independently hydrogen, or methyl; and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two loweralkyl substituents;

or an acid-addition salt thereof.

These compounds are useful as intermediates in the preparation of thecompounds of the invention having Formula III hereinabove.

The invention resides, in another of its composition aspect, in thechemical compounds having Formula IX hereinbelow ##STR22## wherein R islower-alkyl;

A is carbonyl, CHOH or methylene;

R₂ is hydrogen or methyl, and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two loweralkyl substituents;

or an acid-addition salt thereof.

These compounds are useful as intermediates in the preparation of thecompounds of Formula IV hereinabove. The amino ketones (Formula IX, A iscarbonyl) are useful as intermediates in the preparation of both thecorresponding amino alcohols (Formula IX, A is CHOH) and the amines ofFormula IX wherein A is methylene. The amino alcohols (Formula IX, A isCHOH) are also valuable intermediates in the preparation of the aminesof Formula IX wherein A is methylene.

In another composition aspect the invention resides in the compoundshaving Formula X hereinbelow ##STR23## wherein the RO substituentoccupies either position 6 or position 7 of the naphthalene nucleus;

R is lower-alkyl or benzyl;

R₂, R₅ and R₆ are each hydrogen or methyl, provided that when R₂ ismethyl R₅ and R₆ are hydrogen;

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two loweralkyl substituents;

or an acid-addition salt thereof.

These compounds are useful as cardiotonic agents and are useful also asintermediates in preparing the compounds of Formula V hereinabove.

Another composition aspect of the invention resides in the compoundshaving Formula XI hereinbelow ##STR24## wherein the side chainrepresented by --CHX-CHR₂ -NR₃ R₄ occupies either position 1 or position2 of the naphthalene nucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms;

X is chlorine or bromine;

Q and R₂ are independently hydrogen or methyl, and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two lower-alkyl substituents;

or an acid-addition salt thereof.

The halo amines (Formula XI) are useful as intermediates in thepreparation of the amines of Formula VI hereinabove wherein A ismethylene.

Another composition aspect of the invention resides in the compoundshaving Formula XII hereinbelow ##STR25## wherein the side chainrepresented by --CH₂ CONR₃ R₄ occupies either position 1 or position 2of the naphthalene nucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms;

Q is hydrogen or methyl, and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two lower-alkyl substituents.

These amides are useful as intermediates in the preparation of thecorresponding amines of Formula VI hereinabove, wherein A is methyleneand R₂ is hydrogen.

In a further composition aspect the invention resides in the compoundshaving Formula XIII hereinbelow ##STR26## wherein the side chainrepresented by --COCHR₂ X occupies either position 1 or position 2 ofthe naphthalene nucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms;

Q and R₂ are independently hydrogen or methyl; and

X is chlorine, bromine or iodine.

The halo ketones (Formula XIII) are useful as intermediates in thepreparation of the corresponding amino ketones of Formula VI hereinabovewherein A is carbonyl.

Another composition aspect of the invention resides in the compoundshaving Formula XIV hereinbelow ##STR27## wherein the side chainrepresented by --CH₂ CH₂ X occupies either position 1 or position 2 ofthe naphthalene nucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms;

Q is hydrogen or methyl; and

X is chlorine, bromine or p-toluenesulfonate.

These compounds are useful as intermediates in the preparation of theamines of Formula VI hereinabove wherein A is methylene and R₂ ishydrogen.

In another composition aspect the invention resides in the compoundshaving Formula XV hereinbelow ##STR28## wherein the side chainrepresented by ##STR29## occupies either position 1 or position 2 of thenaphthalene nucleus; R is lower-alkyl or benzyl, or both R groupstogether constitute a methylene group bonded to both oxygen atoms; and

Q, R₅ and R₆ are independently hydrogen or methyl.

These nitriles are useful as intermediates in the preparation of theamines having Formula VI hereinabove, wherein A is CR₅ R₆ and R₂ ishydrogen. The nitriles of Formula XV wherein R₅ and R₆ are hydrogen arealso useful as intermediates in the preparation of the nitriles ofFormula XV wherein one of or both R₅ and R₆ are methyl.

In another composition aspect the invention resides in the compoundshaving Formula XVI hereinbelow ##STR30## wherein the side chainrepresented by --CONR₃ R₄ occupies either position 1 or position 2 ofthe naphthalene nucleus;

Q is hydrogen or methyl;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms;

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two lower-alkyl substituents, provided thatwhen the side chain --CONR₃ R₄ occupies position 2, R₃ and R₄ are notboth hydrogen.

These naphthamides are useful as intermediates in the preparation of theamines of Formula VI hereinabove wherein A is a direct linkage; andwherein R₃ and R₄ are not both hydrogen when the aminomethyl group --CH₂NR₃ R₄ occupies position 2 of the naphthalene nucleus.

In another composition aspect the invention resides in the compoundshaving Formula XVII hereinbelow ##STR31## wherein the side chainrepresented by ##STR32## occupies either position 1 or position 2 of thenaphthalene nucleus; R is lower-alkyl, and

R₅ and R₆ are independently hydrogen or methyl.

These nitriles are useful as intermediates in the preparation of thecorresponding amines of Formula VIII hereinabove. The nitriles (FormulaXVII) wherein R₅ and R₆ are hydrogen are also useful as intermediates inthe preparation of the nitriles of Formula XVII wherein R₅ and/or R₆represent methyl.

Another composition aspect of the present invention resides in thecompounds having Formula XVIII hereinbelow ##STR33## wherein R islower-alkyl or benzyl.

The nitro olefins (Formula XVIII) are useful as intermediates in thepreparation of the amines of Formula IX hereinabove wherein A ismethylene and R₂, R₃ and R₄ are hydrogen.

A further composition aspect of the invention resides in the compoundshaving Formula XIX hereinbelow ##STR34## wherein R is lower-alkyl orbenzyl;

R₂ is hydrogen or methyl and

X is chlorine, bromine or iodine.

These halo ketones are useful as intermediates in the preparation of thecorresponding amino ketones of Formula IX hereinabove wherein A iscarbonyl.

A further composition aspect of the invention resides in the compoundshaving Formula XX hereinbelow ##STR35## wherein the RO substituentoccupies either position 6 or position 7 of the naphthalene nucleus;

R is lower-alkyl or benzyl;

R₅ is hydrogen or methyl, and

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two lower-alkyl substituents.

These amides are useful as intermediates in the preparation of thenaphthalenealkylamines of Formula X hereinabove, wherein R₂ and R₆ arehydrogen.

Another composition aspect of the invention resides in the chemicalcompounds having the Formula XXI hereinbelow ##STR36## wherein the ROsubstituent occupies either position 6 or position 7 of the naphthalenenucleus;

R is lower-alkyl or benzyl, and

R₅ and R₆ are independently hydrogen or methyl.

The nitriles (Formula XXI) are useful as intermediates in thepreparation of the naphthalenealkylamines of Formula X hereinabove,wherein R₂ is hydrogen. Furthermore, the nitriles (Formula XXI) whereinR₅ and R₆ are hydrogen are useful as intermediates in the preparation ofnitriles of Formula XXI wherein either one of or both R₅ and R₆ aremethyl.

A further composition aspect of the invention resides in the compoundshaving the Formula XXII hereinbelow ##STR37## wherein the RO substituentoccupies either position 6 or position 7 of the naphthalene nucleus;

A is carbonyl or CHOH;

R is lower-alkyl or benzyl;

R₃ and R₄ are independently hydrogen, lower-alkyl, benzyl, aryl or NR₃R₄ is pyrrolidino, piperidino, hexamethyleneimino, morpholino or any ofthese having from one to two lower-alkyl substituents.

These compounds are useful as intermediates in the preparation of theamines of Formula X wherein R₅ and R₆ are hydrogen and R₂ is methyl.Furthermore, the amino ketones (Formula XXII) wherein A is C═O areuseful as intermediates in the preparation of the corresponding aminoalcohols of Formula XXII wherein A is CHOH.

The invention in another composition aspect resides in the compoundshaving Formula XXIII hereinbelow ##STR38## wherein the side chainrepresented by ##STR39## occupies either position 1 or position 2 of thenaphthalene nucleus; R is lower-alkyl or benzyl; or both R groupstogether constitute a methylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl.

These hydroxy amines are useful as intermediates in the preparation ofthe halo amines of Formula XI hereinabove wherein R₂ is methyl and R₃and R₄ are hydrogen.

Another composition aspect of this invention resides in the compoundshaving Formula XXIV hereinbelow ##STR40## wherein the side chainrepresented by --CH₂ COX occupies either position 1 or position 2 of thenaphthalene nucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms;

Q is hydrogen or methyl, and

X is chlorine or bromine.

These acid halides are useful as intermediates in the preparation of thenaphthaleneacetamides of Formula XII hereinabove.

In another composition aspect, the invention resides in the compoundshaving Formula XXV hereinbelow ##STR41## wherein the side chainrepresented by --CH₂ CH₂ OH occupies either position 1 or position 2 ofthe naphthalene nucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl.

These alcohols are useful as intermediates in the preparation of thecorresponding halides of Formula XIV hereinabove.

Another composition aspect of the invention resides in the compoundshaving Formula XXVI hereinbelow ##STR42## wherein the chloromethylsubstituent occupies either position 1 or position 2 of the naphthalenenucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl.

These halides are useful as intermediates in the preparation of thenitriles of Formula XV hereinabove wherein R₅ and R₆ are hydrogen.

A further composition aspect of the invention resides in the compoundshaving Formula XXVII hereinbelow ##STR43## wherein the COX substituentoccupies either position 1 or position 2 of the naphthalene nucleus;

X is chlorine or bromine;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl.

These acid chlorides are useful as intermediates in the preparation ofamides having Formula XVI hereinabove.

In another composition aspect the invention resides in the compoundshaving Formula XXVIII hereinbelow ##STR44## wherein R is lower-alkyl.

These nitriles are useful as intermediates in the preparation ofnitriles having Formula XVII hereinabove, wherein the side chainrepresented by --CR₅ R₆ CN occupies position 1 of the naphthalenenucleus, and R₅ and R₅ are hydrogen.

A further composition aspect of the invention resides in the compoundshaving Formula XXIX hereinbelow ##STR45## wherein R is lower-alkyl.

These halides are valuable intermediates in the preparation of thenitriles of Formula XVII hereinabove, wherein the side chain representedby --CR₅ R₆ CN occupies position 2 of the naphthalene nucleus and R₅ andR₆ are hydrogen.

In a further composition aspect the invention resides in the compoundshaving Formula XXX hereinbelow ##STR46## wherein the RO substituentoccupies either position 6 or position 7 of the naphthalene nucleus; and

R is lower-alkyl or benzyl.

These nitriles are useful as intermediates in the preparation of thecompounds of Formula XXI hereinabove wherein R₅ and R₆ are hydrogen.

In still another composition aspect, the invention resides in thechemical compounds having the Formula XXXI hereinbelow ##STR47## whereinthe side chain represented by ##STR48## occupies either position 1 orposition 2 of the naphthalene nucleus; R is lower-alkyl, benzyl; or bothR groups together constitute a methylene group bonded to both oxygenatoms;

Q is hydrogen or methyl, and

A is carbonyl or CHOH.

These oximes are useful as intermediates in the preparation of thehydroxy amines of Formula XXIII hereinabove. The oximes (Formula XXXI)wherein A is carbonyl are also useful as intermediates in thepreparation of oximes (Formula XXXI) wherein A is CHOH.

Another composition aspect of the invention resides in the compoundshaving Formula XXXII hereinbelow ##STR49## wherein the side chainrepresented by CH₂ CO₂ H occupies either position 1 or position 2 of thenaphthalene nucleus;

R is hydrogen, lower-alkyl or benzyl; or both R groups togetherconstitute a methylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl.

These acids are useful as intermediates in the preparation of thecorresponding acid chlorides of Formula XXIV hereinabove. The acids arealso useful as intermediates in the preparation of the alcohols ofFormula XXV hereinabove. The acids wherein R is hydrogen are useful asintermediates in the preparation of the acids of Formula XXXII wherein Ris lower-alkyl or benzyl, or wherein both R groups together constitute amethylene group bonded to both oxygen atoms.

The invention in another composition aspect resides in the compoundshaving Formula XXXIII hereinbelow ##STR50## wherein the hydroxymethylsubstituent occupies either position 1 or position 2 of the naphthalenenucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl.

These alcohols are useful as intermediates in the preparation of thechloromethyl compounds of Formula XXVI hereinabove.

A further composition aspect of the invention resides in the compoundshaving Formula XXXIV hereinbelow ##STR51## wherein R is lower-alkyl.

These alcohols are useful as intermediates in the preparation of thehalides of Formula XXIX hereinabove.

Another composition aspect of the invention resides in thethiomorpholides having the Formula XXXV hereinbelow ##STR52## whereinthe side chain represented by ##STR53## occupies either position 1 orposition 2 of the naphthalene nucleus; R is lower-alkyl or benzyl; orboth R groups together constitute a methylene group bonded to bothoxygen atoms, and

Q is hydrogen or methyl.

These thiomorpholides are useful as intermediates in the preparation ofthe carboxylic acids of Formula XXXII hereinabove.

In another composition aspect the invention resides in the compoundshaving the Formula XXXVI hereinbelow ##STR54## wherein the carboxylgroup occupies either position 1 or position 2 of the naphthalenenucleus;

R is lower-alkyl or benzyl; or both R groups together constitute amethylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl provided that when the carboxyl group occupiesposition 2, Q is methyl.

These acids are useful as intermediates in the preparation of thecorresponding acid chlorides of Formula XXVII as well as the alcohols ofFormula XXXIII hereinabove.

In another composition aspect the invention resides in the compoundshaving Formula XXXVII hereinbelow ##STR55## wherein R is lower-alkyl.

These aldehydes are useful as intermediates in the preparation of thealcohols of Formula XXXIV hereinabove.

A further composition aspect of the invention resides in the compoundshaving Formula XXXVIII hereinbelow ##STR56## wherein R is lower-alkyl orbenzyl; or both R groups together constitute a methylene group bonded toboth oxygen atoms;

Q and R₂ are independently hydrogen or methyl, and

the side chain represented by --COCH₂ R₂ occupies either position 1 orposition 2 of the naphthalene nucleus, provided that when said sidechain occupies position 2, Q is methyl.

These ketones are useful as intermediates in the preparation of thethiomorpholides of Formula XXXV hereinabove. They are also useful asintermediates in the preparation of the halo ketones of Formula XIII,the oximes of Formula XXXI and the naphthoic acids of Formula XXXVIhereinabove.

Another composition aspect of the invention resides in the compoundshaving Formula XXXIX hereinbelow ##STR57## wherein R is lower-alkyl.

These aldehydes are useful as intermediates in the preparation of thealdehydes of Formula XXXVII hereinabove.

In another composition aspect of the invention resides in the compoundshaving Formula XL hereinbelow ##STR58## wherein R is lower-alkyl, and

A is carbonyl or CHOH.

The ketones (Formula XL, A is carbonyl) are useful as intermediates inthe preparation of the corresponding alcohols (Formula XL, A is CHOH)which are in turn useful as intermediates in the preparation of thealdehydes of Formula XXXIX hereinabove.

Preparation of Final Products

Certain of the final products of the invention, namely, the compounds ofFormula I wherein R═R₁ ═H and A is C═O, a direct linkage, or CR₅ R₆ asdefined herinabove, the compounds of Formulas II and III wherein R═R₁═H, the compounds of Formula IV wherein R═R₁ ═H and A is C═O or CH₂ andthe compounds of Formula V wherein R═H are conveniently prepared bycleavage of the corresponding RO-substituted compounds of Formulas VI,VII, VIII, IX and X, respectively. This cleavage is effected through theagency of acidic reagents such as, for example, hydrogen chloride,hydrogen bromide, hydrogen iodide, boron tribromide, aluminum chlorideor aluminum bromide. In the case where RO is benzyloxy, cleavage canalso be effected with trifluoroacetic acid or by catalytichydrogenolysis using hydrogen and a suitable catalyst such as, forexample, palladium-on-carbon or Raney nickel. A preferred mode ofcarrying out the cleavage reaction consists of heating theRO-substituted compound with hydrogen chloride or hydrogen bromide in anaqueous medium at a temperature of from 80° C. to 130° C., preferably atthe reflux temperature of the reaction mixture, for a period of fromone-half to three hours.

It will be obvious that the above-described cleavage methods, as appliedto the RO groups bound to the naphthalene ring, also effect similarcleavage of RO groups which may be bound at other points in themolecule. For example, compounds of the Formula VII wherein Z is methoxyare converted to the compounds of Formula II wherein Z is hydroxy.

The amino alcohols of Formula I wherein A is CHOH are prepared byreducing the corresponding amino ketones of Formula I wherein A iscarbonyl. The reduction by catalytic hydrogenation can be effected inthe presence of a noble metal catalyst such as platinum or palladium.The reaction is conveniently carried out by shaking a solution of theamino ketone in the form of its acid-addition salt in DMF at 20°-60° C.under a hydrogen pressure of from 20-50 psi in the presence of aneffective amount of palladium-on-carbon. The hydrogenation is continueduntil the theoretical amount of hydrogen is absorbed. A hydrogenationtime of six hours or less is generally satisfactory. This same reductiveprocedure also effects reduction of the ketones of Formula IV (A is C═O)to the corresponding alcohols of Formula IV (A is CHOH).

It will be appreciated that benzyl substituents attached to the nitrogenatom of the starting amino ketone of Formula I (A is C═O; either one ofor both R₃ and R₄ =benzyl) are cleaved during the above-describedcatalytic hydrogenation, with the additional absorption of oneequivalent of hydrogen per benzyl group.

The esters of the invention having the Formulas I (A is C═O, a directlinkage or CR₅ R₆ as defined hereinabove), II, III and IV (A is C═O orCH₂) wherein in each of the said formulas, at least one of R and R₁ islower-alkanoyl or aroyl while the other is hydrogen or wherein both Rand R₁ are lower-alkanoyl or aroyl, as well as the esters of Formula Vwherein R is lower-alkanoyl or aroyl, are obtained by acylating thecorresponding hydroxy compounds of Formulas I, II, III and IV,respectively, wherein R═R₁ ═H and V wherein R═H with an appropriate acidhalide in a strongly acidic medium at a temperature of from -10° C. to30° C. A reaction time of six hours or less is generally satisfactory.The reaction is conveniently carried out by reacting the appropriatehydroxy-substituted starting compound, in the form of its acid-additionsalt, with an acid chloride in trifluoroacetic acid at 0° C. to 25° C.for about three to four hours.

It will be obvious that the above-described esterification of hydroxylgroups bound to the naphthalene ring will also effect esterification ofother hydroxyl groups which may be present in the molecule. For example,esterification of the compounds of Formula II wherein R and R₁ arehydrogen, and Z is hydroxy will produce the esters of Formula II whereinR and R₁ are lower-alkanoyl or aroyl and wherein Z is lower-alkanoyloxyor aroyloxy.

Preparation of Intermediates

The RO-substituted naphthalenealkylamines having Formulas VI and IXwherein A is methylene are obtained by catalytic hydrogenation of thecorresponding ketones of Formulas VI and IX wherein A is carbonyl. Thereduction is conveniently carried out by shaking a solution of saidketone in the form of its acid-addition salt in a suitable solvent as,for example, dimethylformamide or aqueous acetic acid, at 20° C. to 80°C. under a hydrogen pressure of from 20-50 psi in the presence of astrong acid as, for example, hydrochloric and a noble metal catalystsuch as palladium. The hydrogenation is continued until the theoreticalamount of hydrogen is absorbed. A hydrogenation time of fifteen hours orless is generally satisfactory.

The amino ketones of Formula VI and IX (A is carbonyl) having one or twobenzyl substituents bound to the nitrogen atom undergo concomitantdebenzylation under the above-described reduction conditions. Oneadditional mole of hydrogen is absorbed per benzyl group.

The above reaction conditions are also effective in reducing thealkoxy-substituted amino alcohols of Formula VI and IX wherein A is CHOHto the corresponding alkoxy-substituted naphthalenealkylamines ofFormulas VI and IX wherein A is methylene.

It will be apparent that the above-described catalytic reduction ofeither the amino ketones (Formulas VI and IX wherein A is carbonyl) orthe amino alcohols (Formulas VI and IX wherein A is CHOH) wherein R isbenzyl proceeds with cleavage of the benzyl groups to give thecorresponding hydroxy-substituted compounds of Formulas I and IV whereinR and R₁ are hydrogen and A is methylene.

The RO-substituted amino alcohols of Formulas VI and IX wherein A isCHOH are obtained by reducing the corresponding amino ketones ofFormulas VI and IX wherein A is carbonyl with an appropriate reducingagent in a suitable solvent as, for example, lithium aluminum hydride intetrahydrofuran, ether or dioxane; diborane in tetrahydrofuran ordiglyme or by hydrogenation in the presence of a noble metal cataystsuch as palladium or platinum. The reaction is conveniently carried outby treating said amino ketones with lithium aluminum hydride inrefluxing tetrahydrofuran for from five to twenty hours. Alternatively,the reduction is effected by shaking a solution of the amino ketone inthe form of its acid-addition salt in a suitable solvent as, forexample, dimethylformamide, at 20° C. to 50° C. under a hydrogenpressure of from 20-50 psi in the presence of a noble metal catalystsuch as palladium. The hydrogenation is continued until the theoreticalamount of hydrogen is absorbed. A hydrogenation time of six hours orless is generally satisfactory.

It will be apparent that catalytic reduction of the amino ketones ofFormulas VI or IX (A is carbonyl) wherein R is benzyl proceeds withcleavage of the benzyl groups to give the hydroxy-substituted aminoalcohols of Formulas I or IV wherein A is CHOH, and R and R₁ arehydrogen. Accordingly, when it is desired to prepare the RO-substitutedamino alcohols VI or IX (A is CHOH) wherein R is benzyl a chemicalreduction procedure is employed.

Since the amino ketones of Formulas VI and IX wherein A is carbonyl arereduced to the corresponding amino alcohols (Formulas VI and IX whereinA is CHOH) which in turn are reduced to the amines (Formulas VI and IXwherein A is methylene) it is apparent that the reduction of the aminoketones (Formulas VI and IX wherein A is carbonyl) to the amines(Formulas VI and IX wherein A is methylene) may optionally be carriedout either in a single process or in a stepwise procedure.

The amino ketones having the Formulas VI and IX wherein A is carbonylare conveniently prepared by treating the halo ketones of Formulas XIIIand XIX in acetonitrile with an excess of ammonia or a primary orsecondary amine at from -30° C. to 90° C. for about two to twenty hours.

The halo ketones of Formulas XIII and XIX are conveniently prepared byhalogenating the appropriate acetonaphthones (Formulas XXXVIIIhereinabove and XLI hereinbelow) with a halogen as, for example,chlorine or bromine in chloroform at approximately 25° C. for about twohours. ##STR59## wherein R is lower-alkyl or benzyl, and

R₂ is hydrogen or methyl.

The di(RO)acetonaphthones of Formula XXXVIII are conveniently preparedby treating the di(RO)naphthalenes of Formula XLII hereinbelow ##STR60##wherein R is lower-alkyl or benzyl; or both R groups together constitutea methylene group bonded to both oxygen atoms, and

Q is hydrogen or methyl;

in an inert solvent as, for example, sym-tetrachloroethane ornitrobenzene, at a temperature of about 0° C. to ambient temperatures,with an appropriate acid halide, e.g. acetyl chloride or propionylchloride in the presence of a Lewis acid such as aluminum chloride for aperiod of from one to three hours. The reaction yields both the 1- andthe 2-isomer.

The di(RO)acetonaphthones of Formula XLI are a known class of compoundsprepared by reacting lower-alkanoyl halides with 1,5-di(RO)naphthalenesunder Friedel-Crafts conditions.

Alternatively the halo ketones of Formulas XIII and XIX are obtained byreacting the appropriate di(RO)naphthalenes, e.g. XLII and1,5-di(RO)naphthalene with α-haloalkanoyl halides as, for example,chloroacetyl chloride, bromoacetyl bromide, α-bromopropionyl bromide andthe like in the presence of a Lewis acid catalyst such as aluminumchloride or aluminum bromide in an appropriate solvent as, for example,dichloromethane or chloroform. The reaction is conveniently carried outby treating a di(RO)naphthalene in dichloromethane with the appropriateα-chloroalkanoyl chloride in he presence of aluminum chloride atapproximately 25° C. for about 24 to 48 hours.

The α-iodoketones (Formulas XIII and XIX, X═I) are obtained by reactingthe corresponding chlorides or bromides with sodium iodide in refluxingacetone.

The di(RO)naphthalenes (Formula XLII) and 1,5-di(RO)naphthalenes areknown classes of compounds prepared by the classical Williamson ethersynthesis from the appropriate naphthalenediols and lower-alkyl halides.

The compounds of Formula VI wherein A is methylene are also prepared bycatalytic hydrogenation of the halo amines of Formula XI. The reactionis conveniently carried out by shaking a solution of the halo amine(Formula XI), in the form of its acid-addition salt, indimethylformamide at approximately 25° C. under a hydrogen pressure offrom 22-50 psi in the presence of an effective amount ofpalladium-on-carbon. The hydrogenation is continued until thetheoretical amount of hydrogen is absorbed. A hydrogenation time of sixhours or less is generally satisfactory.

It will be appreciated that the above-described catalytic reduction ofhalo amines of Formula XI wherein R is benzyl will also effectconcomitant debenzylation to produce the hydroxy-substituted amines ofFormula I wherein A is methylene, and R and R₁ are hydrogen.

The halo amines of Formula XI are obtained by treating the correspondinghydroxy amines (Formula VI wherein A is CHOH; and Formula XXIII) with athionyl halide in refluxing chloroform for about one hour.

The hydroxy amines of Formula XXIII are obtained by catalytichydrogenation of the oximino ketones of Formula XXXI (A is C═O) or theoximino alcohols XXXI (A is CHOH) in ethanol at about 25° C. to 65° C.under a hydrogen pressure of 20-50 psi in the presence of an effectiveamount of palladium and an excess of hydrochloric acid. Thehydrogenation is continued until the theoretical amount of hydrogen isabsorbed. A hydrogenation time of six hours or less is generallysatisfactory.

It will be apparent that catalytic reduction of either the oximinoketones (Formula XXXI; A is carbonyl) or the oximino alcohols (FormulaXXXI; A is CHOH) wherein R is benzyl results in the cleavage of thebenzyl groups to produce the hydroxy-substituted compounds (FormulaXXIII) wherein R is replaced by hydrogen. Accordingly, the hydroxyamines of Formula XXIII wherein R is benzyl are prepared by reduction ofthe oximino ketones of Formula XXXI (A is carbonyl) or the oximinoalcohols (Formula XXXI; A is CHOH) with a suitable chemical reducingagent in an appropriate solvent, e.g. lithium aluminum hydride in ether,dioxane or tetrahydrofuran.

The oximino alcohols of Formula XXXI (A is CHOH) are prepared byreduction of the corresponding oximino ketones of Formula XXXI (A isC═O) with an appropriate chemical reducing agent in an appropriatesolvent, e.g. sodium borohydride in a lower-alkanol, or diglyme,optionally in the presence of an alkali metal hydroxide at a temperatureof about 0° C. to 50° C. The reduction is conveniently carried out bytreating said oximino ketone in ethanol containing sufficient sodiumhydroxide to dissolve the oxime with sodium borohydride at ambienttemperatures for about three hours.

The oximino ketones of Formula XXXI (A is C═O) are obtained by treatingthe di(RO)acetonaphthones of Formula XXXVIII (R₂ ═CH₃), in ether orbenzene or a mixture thereof, with an alkyl nitrite, e.g. butyl nitrite,amyl nitrite or iso-amyl nitrite in the presence of an acid such ashydrogen chloride or hydrogen bromide. The reaction is convenientlycarried out by treating acid oximino ketone in a refluxing mixture ofether and benzene with a slight excess of amyl nitrite in the presenceof hydrogen chloride for about five hours.

The di(RO) compounds of Formula VI wherein A is methylene and R₂ ishydrogen are obtained by reducing the di(RO)naphthaleneacetamides ofFormula XII with a suitable chemical reducing agent in an appropriatesolvent, e.g. diborane in tetrahydrofuran or diglyme; or lithiumaluminum hydride in tetrahydrofuran, ether or dioxane, at 0° C. to 65°C. for from about one to about 24 hours. The reaction is convenientlycarried out by heating said amide with diborane in tetrahydrofuran atthe reflux temperature for from about six to about eight hours.

The di(RO)naphthaleneacetamides of Formula XII are obtained by reactingthe corresponding acid halides of Formula XXIV with an excess of anappropriate amine of Formula XLIII ##STR61## wherein R₃ and R₄ have thepreviously given meaning; in a suitable solvent such as ether, benzeneor chloroform or in a heterogeneous mixture of one of these solventswith water at from about 0° C. to ambient temperatures. The reaction isconveniently carried out by treating an aqueous solution of at least twoequivalents of the amine (Formula XLIII) with an ethereal solution ofthe acid chloride (Formula XXIV) with ice-bath cooling.

The di(RO)naphthaleneacetyl halides of Formula XXIV are prepared fromthe corresponding carboxylic acids (Formula XXXII) by reaction in asuitable solvent, e.g. benzene, chloroform or ethylene dichloride withan appropriate thionyl halide or phosphorous oxyhalide. The reaction isconveniently carried out by reacting the carboxylic acids (FormulaXXXII) in chloroform with an excess of thionyl halide at 25° C. to 50°C. for about one to two hours.

The di(RO)naphthaleneacetic acids of Formula XXXII are obtained bytreating the thiomorpholides of Formula XXXV with refluxing aqueoussodium hydroxide for from about five to ten hours.

The thiomorpholides (Formula XXXV) in turn, are prepared by treating theappropriate di(RO)acetonaphthones of Formula XXXVIII (R₂ ═H) with sulfurmorpholine (optionally in the presence of an acid catalyst such asp-toluenesulfonic acid) for from about three to about ten hours.

Alternatively, the di(RO) compounds of Formula VI wherein A is methyleneand R₂ is hydrogen are obtained by reacting the halide or tosylate ofFormula XIV in a suitable solvent, e.g. a lower-alkanol, acetonitrile,tetrahydrofuran or dimethylformamide with an appropriate amine ofFormula XLIII in the presence of an acid-acceptor, e.g. an alkali metalcarbonate, or an excess of the amine (Formula XLIII). The reaction isconveniently carried out by treating a solution of at least twoequivalents of said amine in dimethylformamide with a halide or tosylate(Formula XIV) with ice-bath cooling.

The intermediate halide and tosylates (Formula XIV) are prepared fromthe corresponding alcohols (Formula XXV) by reaction withp-toluenesulfonyl chloride in pyridine with ice-bath cooling. Thereaction produces a mixture of the chloride (Formula XIV, X═Cl) and thetosylate ##STR62##

The naphthaleneethanols (Formula XXV) are prepared by reducing thenaphthaleneacetic acids of Formula XXXII with a suitable chemicalreducing agent in an appropriate solvent, e.g. lithium aluminum hydridein ether, tetrahydrofuran or dioxane; or diborane in tetrahydrofuran ordiglyme, at temperatures of from about 0° C. to about 80° C. forapproximately one to eighteen hours. The reaction is convenientlycarried out by treating said acid in tetrahydrofuran with lithiumaluminum hydride on the steam bath for approximately one to two hours.

The di(RO) compounds of Formula VI wherein A is CR₅ R₆ and R₂ is H areobtained by reducing the naphthaleneacetonitriles of Formula XV with asuitable chemical reducing agent in a suitable solvent, e.g. lithiumaluminum hydride in tetrahydrofuran, ether or dioxane or with hydrogenin the presence of a suitable catalyst such as Raney nickel in asolution of a lower-alkanol containing ammonia. The reaction isconveniently carried out by treating said nitrile in tetrahydrofuranwith lithium aluminum hydride at the reflux temperature for about twohours.

It is obvious that both of the above-described procedures will affordthe primary amine (Formula VI; A is CR₅ R₆ ; R₂ ═R₃ ═R₄ ═H). In order toobtain secondary and tertiary amines, i.e. amines of Formula VI whereinR₃ and R₄ are substituents other than hydrogen, the above-describedmethod of hydrogenation over Raney nickel is used wherein ammonia isreplaced by a primary or secondary amine bearing the desiredsubstituents R₃ and R₄. Furthermore, catalytic reduction of thosenaphthaleneacetonitriles (Formula XV) wherein R is benzyl will proceedwith cleavage of the benzyl groups to give the hydroxy-substitutedamines of Formula I (A is CR₅ R₆, R₂ ═H) wherein R and R₁ are hydrogen.

The intermediate nitriles (Formula XV, R₅ ═R₆ ═H) are convenientlyprepared by treating the chloromethyl compounds of Formula XXVI withsodium cyanide in dimethyl sulfoxide at temperatures of about 0° C. toambient temperatures for about one-half to about seven hours.

The nitriles so produced may subsequently be treated with an appropriateamount of a methylating agent such as methyl iodide in dimethylformamidein the presence of an appropriate amount of a strong base, e.g. sodiumhydride at about 25° C. to 85° C. for about one to three hours to affordthe nitriles of Formula XV wherein at least one of or both R₅ and R₆ aremethyl.

The chloromethyl compounds (Formula XXVI) are conveniently prepared bytreating the di(RO)naphthalenemethanols of Formula XXXIII in benzenewith hydrogen chloride in he presence of sodium sulfate with ice-bathcooling.

The di(RO)naphthalenemethanols of Formula XXXIII are prepared byreducing the naphthoic acids of Formula XXXVI using the proceduredescribed hereinabove for the preparation of the naphthaleneethanols ofFormula XXV.

The naphthoic acids of Formula XXVI are obtained by oxidizing theacetonaphthones of Formula XXXVIII (R₂ ═H) with a suitable hypohalite inalkaline solution. The reaction is conveniently carried out by treatingsaid acetonaphthones with an excess of 5.25% sodium hypochloritesolution (Chlorox®) in the presence of sodium hydroxide on the steambath for one-half to about six hours.

The di(RO) compounds of Formula VI wherein A is a direct linkage, and R₂is hydrogen are prepared by reducing the di(RO)naphthamides of FormulaXVI with a suitable chemical reducing agent in a suitable solvent, e.g.lithium aluminum hydride in tetrahydrofuran, ether or dioxane; ordiborane in tetrahydrofuran or diglyme at about 25° C. to 85° C. forabout one-half to three hours. The reaction is conveniently carried outby treating said amide in refluxing tetrahydrofuran with lithiumaluminum hydride for about one to about two hours.

The naphthamides of Formula XVI are prepared from the naphthoyl halidesof Formula XXVII using the procedure described hereinabove for thepreparation of the naphthaleneacetamides of Formula XII.

The intermediate naphthoyl halides (Formula XXVII) are prepared from thecorresponding naphthoic acids of Formula XXXVI using the proceduredescribed hereinabove for the preparation of the naphthaleneacetylhalides of Formula XXIV.

The alkoxy-substituted naphthalenealkylamines of Formula VII wherein R₈is hydrogen are conveniently prepared by treating amines of Formulas VI(R₃ ═R₄ ═H) in the form of their acid-addition salts, in methanol with acarbonyl compound of Formula XLIV ##STR63## wherein R₇, Z and n have thepreviously given meanings and sodium cyanoborohydride at a pH of 5.0 to6.0 in the presence of molecular sieves having a pore diameter suitablefor the absorption of water.

The carbonyl compounds of Formula XLIV are a known class of compounds,prepared from readily available materials.

Alternatively, the compounds of Formula VII can be prepared by reactingan amine having Formula XLV ##STR64## wherein R₇, R₈, Z and n have thepreviously given meanings, with a halo ketone of Formula XIIIhereinabove.

The dialkoxynaphthalenealkylamines having the Formula VIII are preparedby reducing the nitriles of Formula XVII with a suitable reducing agentas, for example lithium aluminum hydride, or hydrogen in the presence ofa suitable catalyst such as Raney nickel. The reaction is convenientlycarried out by shaking a solution of nitrile and ammonia or a primary orsecondary amine in methanol at 20° C. to 50° C. under a hydrogenpressure of 20-50 psi in the presence of Raney nickel. The hydrogenationis continued until the theoretical amount of hydrogen is absorbed.

The dialkoxynaphthalene-1-acetonitriles of Formula XVII (CR₅ R₆ CN atposition 1; R₅ ═R₆ ═H) are prepared by oxidizing the unsaturatednitriles of Formula XXVIII. The reaction is conveniently carried out bytreating a solution of nitrile of Formula XXVIII in refluxing carbontetrachloride with a molar equivalent of N-bromosuccinimide for abouttwo to about four hours followed by treatment with a base such as analkali metal hydroxide, carbonate or bicarbonate or a tertiary amine,e.g. N,N-dimethylaniline.

The unsaturated nitriles of Formula XXVIII are prepared by treating aglyme solution of the tetralones having the Formula XLVI hereinbelowwherein R is lower-alkyl ##STR65## with diethyl phosphoroacetonitrileand sodium hydride at about 20° C. to 30° C. for approximately one totwenty-four hours.

The tetralones of Formula XLVI are a known class of compounds obtainedfrom readily available materials.

The dialkoxynaphthalene-2-acetonitriles of Formula XVII (CR₅ R₆ CN atposition 2; R₅ ═R₆ ═H) are prepared from thechloromethyldialkoxynaphthalenes of Formula XXIX using the proceduredescribed hereinabove for the preparation of the6,7-dialoxynaphthaleneacetonitriles of Formula XV.

The intermediate chloromethyl compounds of Formula XXIX are obtainedfrom the corresponding hydroxymethyl compounds of Formula XXIV using theprocedure described hereinabove for the preparation of the chloromethylderivatives of Formula XXVI.

The hydroxymethyl compounds of Formula XXXIV are prepared by reducingthe corresponding naphthaldehydes of Formula XXXVII using a proceduresimilar to that described hereinbelow for the preparation of the hydroxyacetals of Formula XL wherein A is CHOH.

The naphthaldehydes of Formula XXXVII are obtained by oxidizing thedihydronaphthaldehydes of Formula XXXIX. The reaction is convenientlycarried out by irradiating a solution of said dihydronaphthaldehyde andN-bromosuccinimide in carbon tetrachloride at the reflux temperature fora period of from about three to about five hours.

The dihydronaphthaldehydes of Formula XXXIX in turn are obtained by thesimultaneous dehydration-hydrolysis of the hydroxy acetals of Formula XL(A is CHOH). The reaction is conveniently carried out by treating saidhydroxy acetal in acetic acid with a mixture of water and concentratedsulfuric acid at ambient temperatures for about two hours.

The hydroxy acetals of Formula XL (A is CHOH) are obtained by reducingthe corresponding ketones (Formula XL; A is C═O) with a suitablechemical reducing agent in an appropriate solvent such as lithiumaluminum hydride in tetrahydrofuran, ether or dioxane; or sodiumborohydride in a lower-alkanol, at a temperature of about 0° C. to 50°C. for a period of from about one to about three hours. The reaction isconveniently carried out by treating said ketone with excess sodiumborohydride in 2-propanol at about ambient temperature for approximatelytwo hours.

The keto acetals of Formula XL (A is C═O) are obtained by acetalizationof the hydroxymethylene ketones of Formula XLVII hereinbelow wherein Ris lower-alkyl ##STR66## The reaction is conveniently carried out bytreating a benzene solution of said hydroxymethylene ketone with excessethylene glycol in the presence of an acid catalyst such asp-toluenesulfonic acid and removing the water formed therefrom byazeotropic distillation.

The hydroxymethylene ketones of Formula XLVII are a known class ofcompounds prepared from readily available materials.

The 4,8-di(RO) compounds of Formula IX wherein A is CH₂, and R₂ ═R₃ ═R₄═H are prepared by reducing the nitro olefins of Formula XVIII with asuitable reducing agent in a suitable solvent, e.g. lithium aluminumhydride in tetrahydrofuran, ether or dioxane; or with hydrogen in thepresence of a suitable noble metal catalyst such as palladium orplatinum. The reduction is conveniently carried out by treating thenitro olefin of Formula XVIII in refluxing tetrahydrofuran with excesslithium aluminum hydride for about two to about six hours.

It will be apparent that catalytic reduction of the nitro olefins ofFormula XVIII wherein R is benzyl will result in cleavage of the benzylgroups producing the amines of Formula IV (A is CH₂, R₂ ═R₃ ═R₄ ═H)wherein R and R₁ are hydrogen.

The nitro olefins of Formula XVIII are obtained by treating the4,8-di(RO)-1-naphthaldehydes of Formula XLVIII (R=lower-alkyl or benzyl)hereinbelow ##STR67## in refluxing acetic acid with an excess ofnitromethane in the presence of ammonium acetate for about four to eighthours.

The aldehydes of Formula XLVIII are a known class of compounds preparedfrom readily available materials.

The compounds of Formula X wherein R₂ ═R₆ ═H are prepared by reducingthe corresponding naphthaleneacetamides of Formula XX using either theprocedure described hereinabove for the reduction of amides of FormulaXII or the procedure described for the reduction of amides of FormulaXVI.

The naphthaleneacetamides of Formula XX are obtained from thenaphthaleneacetyl chloride of Formula XLIX (R=lower-alkyl or benzyl, R₂═H or CH₃) hereinbelow ##STR68## using the procedure describedhereinabove for the preparation of the naphthaleneacetamides of FormulaXII.

The naphthaleneacetyl chlorides of Formula XLIX are a known class ofcompounds prepared from readily available materials.

Alternatively, the compounds of Formula X wherein R₂ ═H are preparedfrom the corresponding nitriles of Formula XXI using the proceduredescribed hereinabove for the reduction of the nitriles of Formula XVII.

It will be apparent that catalyst reduction of the nitriles of FormulaXXI wherein R is benzyl will result in cleavage of the benzyl group toproduce the naphthols of Formula V (R₂ ═H) wherein R is hydrogen.

The nitriles of Formula XXI wherein one of or both R₅ and R₆ are methylare obtained by methylating the unsubstituted nitriles of Formula XXI(R₅ ═R₆ ═H) using the procedure described hereinabove for themethylation of nitriles of Formula XV (R₅ ═R₆ ═H).

The intermediate nitriles of Formula XXI wherein R₅ ═R₆ ═H are preparedby dehydrogenating the corresponding dihydronaphthaleneacetonitriles ofFormula XXX. The reaction is conveniently carried out by heating asolution of the dihydro derivative in xylene to the reflux temperaturein the presence of a noble metal catalyst such as palladium for abouttwenty to thirty hours.

The dihydronaphthaleneacetonitriles of Formula XXX are prepared byreacting the tetralones of Formula L hereinbelow wherein R islower-alkyl or benzyl; ##STR69## with diethylphosphonoacetonitrile usingthe procedure described hereinabove for the preparation of nitriles ofFormula XXVIII.

The tetralones (Formula L) are a known class of compounds prepared fromreadily available materials.

Alternatively, the (RO)naphthalenealkylamines of Formula X wherein R₅═R₆ ═H, and R₂ ═CH₃ are prepared by reducing the amino ketones ofFormula XXII (A is C═O) or the amino alcohols of Formula XXII (A isCHOH) using the procedures described above for the reduction of theamino ketones of Formulas VI and IX (A is C═O) and the reduction of theamino alcohols of Formulas VI and IX (A is CHOH) to produce the aminesof Formulas VI and IX (A is CH₂). As mentioned in connection with theselatter procedures, catalytic reduction of the amino ketones of FormulaXXII (A is C═O) or the amino alcohols of Formula XXII (A is CHOH)wherein R is benzyl will proceed with cleavage of the benzyl group toproduce the naphthols of Formula V (R₅ ═R₆ ═H) wherein R is hydrogen.

The amino alcohols of Fromula XXII wherein A is CHOH are prepared fromthe corresponding ketones (Formula XXII, A is C═O) using the proceduredescribed hereinabove for the preparation of the amino alcohols ofFormulas VI and IX (A is CHOH).

The amino ketones (Formula XXII, A is C═O) are obtained from the haloketones of Formula LI hereinbelow ##STR70## wherein the RO group mayoccupy either position 6 or position 7 of the naphthalene nucleus;

R is lower-alkyl or benzyl; and

X is chlorine, bromine or iodine using the procedure describedhereinabove for the preparation of the amino ketones of Formula VI (A isC═O) from the corresponding halo ketones (Formula XIII).

The halo ketones of Formula LI are a known class of compounds preparedfrom readily available materials.

As used hereinabove and throughout this specification, the termslower-alkyl and lower-alkanoyl mean such groups containing from one tofour carbon atoms which can be arranged as straight or branched chainsand, without limiting the generality of the foregoing, are illustratedby methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl andthe like for lower-alkyl; and acetyl, propionyl, butyryl, isobutyryl andthe like for lower-alkanoyl.

Aroyl means benzoyl or benzoyl substituted by from one to twolower-alkyl groups.

The compounds of the invention having Formulas I-XI, XXII and XXIII areuseful both in the free base form and in the form of acid-additionsalts, and both forms are within the purview of the invention. Theacid-addition salts are simply a more convenient form for use, and inpractice, use of the salt form inherently amounts to use of the baseform. When the compounds are to be utilized for pharmaceutical purposes,the acids which can be used to prepare the acid-addition salts includepreferably those which produce, when combined with the free base,medicinally acceptable salts, that is, salts whose anions are relativelyinnocuous to the animal organism in medicinal doses of the salts so thatthe beneficial properties inherent in the free base are not vitiated byside effects ascribable to the anions. Appropriate medicinallyacceptable salts within the scope of the invention are those derivedfrom mineral acids such as hydrochloric acid, hydrobromic acid,hydriodic acid and organic acids such as cyclohexanesulfamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, naponic acid (1,4-naphthalenedisulfonic acid),quinic acid and the like giving the hydrochloride, hydrobromide,hydroiodide, nitrate, phosphate, sulfamate, sulfate,cyclohexanesulfamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, naponate and quinate,respectively.

The acid-addition salts of the bases of this invention are obtained bydissolving either or both of the base and the acid separately in wateror an organic solvent and mixing the two solutions or by dissolving boththe base and the acid together in water or an organic solvent. Theresulting acid-addition salt is isolated by filtration, if it isinsoluble in the reaction medium or by concentration of the solution ordilution of the solution with a solvent in which the acid-addition saltis insoluble or only sparingly soluble, or by evaporation of thereaction medium to leave the acid-addition salt as a residue.

Although medicinally acceptable salts of said basic compounds arepreferred for pharmaceutical purposes, all acid-addition salts arewithin the scope of the invention. All acid-addition salts are useful assources of the free base from even if the particular salt per se isdesired only as an intermediate product as for example, when the salt isformed only for purposes of purification or identification, or when itis used as an intermediate in preparing a medicinally acceptable salt byion exchange procedures.

In standard biological test procedures representative examples of finalproducts having Formulas I and V as well as intermediates of Formulas VIand X have been found to possess cardiotonic activity and are useful ascardiotonic agents. The efficacy of these compounds was judged in vitroon the basis of percent increase in contractile force in isolated catatria and papillary muscle, and in vivo on the basis of percent increasein cardiac contractile force in the intact anesthetized dog.

The in vitro test procedures used are described as follows: Male catsweighing from 0.8 to 1.5 kg. were anesthetized with α-chloralose (80mg/kg i.p.). The chest was opened, the heart excised and the two atriadissected. A silk suture was tied to each of two opposite sides of theright atrium. One side of the atrium was tied to a glass rod and thenmounted in a 50 ml. organ bath filled with Tyrode's solution. The secondsuture was attached to a force displacement transducer and the tensionon the atrium was adjusted to 1.5±0.5 grams. The transducer was thenconnected to a Grass polygraph and the force and rate of atrialcontraction was recorded continuously. The left atrium was treatedsimilarly using silver wire instead of silk sutures. The silver wirealso served as a stimulating electrode. Both atria were mounted in thesame bath. The right atrium was beating spontaneously due to thepresence of the sinoatrial node, while the left atrium was stimulatedelectrically at a rate of 3 beats/sec. by suprathreshold rectangularpulses of 5 millisecond duration. The Tyrode's solution bathing theatria was of the following composition (in mM): NaCl 136.87, KCl 5.36,NaH₂ PO₄ 0.41, CaCl₂ 1.80, MgCl₂ 6H₂ O 1.05, NaHCO₃ 11.90, glucose 5.55and EDTA 0.04. The solution was equilibrated with a gas mixtureconsisting of 95% O₂ and 5% CO₂. The preparation was left to equilibratefor one hour before any drug was added. The bathing fluid was changed 3to 4 times during the equilibration time. At the end of equilibrationperiod, the drug dissolved in a vehicle or the vehicle alone was addedto the tissue bath and the full response recorded. When the responsereached a maximum it was abolished by 3 washes at 10 minute intervals oruntil pre-drug values of force of contraction were reached. A doseresponse study of at least 3 doses was done in the same preparation.

Male cats 0.8 to 1.5 kg. were anesthetized with α-chloralose (80 mg/kgi.p.). The chest was opened and the heart excised. The heart was dippedand shaken in Tyrode's solution for the removal of blood from thecavities. The right ventricle was then slit open and the small and thin(about 1 mm. in diameter and 4 to 7 mm. in length) papillary muscleswere dissected out. A silver wire was attached to each of the two endsof the papillary muscle. The ventricular end was attached to a platinumelectrode and mounted in a tissue bath containing Tyrode's solutiondescribed above. The silver wire on the valvular end of the muscle wasattached to a force displacement transducer for the measurement of theforce and rate of muscle contraction. The muscle was stimulated at arate of 3 beats/sec. by suprathreshold rectangular pulses of 5millisecond duration. The rest of the procedure was continued asdescribed above.

The in vivo test procedure used is described as follows: Mongrel dogs ofboth sexes and varying in weight from 9 to 15 kg. were anesthetized with30 mg/kg pentobarbital sodium administered intravenously. The tracheawas exposed and cannulated. The tracheal cannula was then attached to aHarvard respiratory pump using room air. The right femoral artery andvein were cannulated. The arterial cannula was attached to a StathamP23A pressure transducer connected to a Grass polygraph for thecontinuous recording of arterial blood pressure. The venous cannula wasused for the intravenous administration of drugs. Pin electrodes wereattached to the right forelimb and left hindlimb. The electrodes werethen connected to a Grass polygraph for the continuous recording of thestandard limb lead II electrocardiogram. A ventro-dorsal incision at thethird inter-costal space was made, the ribs laterally retracted and thepericardium slit open to expose the myocardium. The base of the aortawas dissected and a flow probe was fitted around it. The flow probe wasattached to a square wave electromagnetic flowmeter (Carolina MedicalElectronics). The flowmeter was then connected to a Grass polygraph forthe continuous recording of aortic blood flow. This flow was used as anindex of cardiac output (actual cardiac output is aortic bloodflow+coronary blood flow). Cardiac contractile force was measured bysuturing a Walton-Brodie strain gauge to the wall of the rightventricle. At the end of the surgical procedure, the animal was left torest and equilibrate for one hour with continuous recording of bloodpressure, EKG, cardiac contractile force and aortic blood flow. Afterthe equilibration period, the vehicle or the drug dissolved in thevehicle was administered and the response of all the parameters measuredto drug administration was recorded continuously for different periodsof time depending on the route of drug administration. Theabove-described test systems were standardized using ouabain,norepinephrine, Isuprel® and dopamine.

The test compounds were subjected to either one of or both the in vitroand in vivo tests. In the in vitro procedure said compounds wereeffective in producing a 25 to 290% increase in atrial force and a 25 to350% increase in papillary muscle force at doses ranging from 0.1 γ/ml.to 30 γ/ml. In the in vivo test the compounds effected an increase offrom 25 to 260% in cardiac contractile force at doses ranging from 10γ/kg. to 100 mg./kg. administered either intravenously orintraduodenally.

Representative examples of the compounds of this invention havingFormulas II, III and IV have been found to be antibacterially active invitro against one or more microorganisms at minimal inhibitoryconcentrations ranging from 15.6 to 500 mcg./ml. Antibacterial activitywas determined using a modification of the Autotiter method described byGoss et al. Applied Microbiology 16 (9), 1,414-1,415 (1968) in which a1,000 mcg./ml. solution of the test compound is prepared. To the firstcup of the Autotray is added 0.1 ml. of the test solution. Activation ofthe Autotiter initiates a sequence of operations by which 0.05 ml. ofthe test compound solution is withdrawn from the cup by a Microtitertransfer loop and diluted in 0.05 ml. of sterile water. Following thisoperation, 0.05 ml. of inoculated double-strength semisynthetic medium(glucose) is added automatically to each cup. The overall operationresults in final drug concentrations ranging from 500 to 0.06 mcg./ml.in twofold decrements. The Autotray is incubated for 18-20 hours at 37°C. at which time the trays are examined visually for growth as evidencedby turbidity, and the concentration of the last sample in the seriesshowing no growth (or no turbidity) is recorded as the minimalinhibitory concentration (MIC) in mcg./ml. The compounds were thustested as solutions against a variety of gram positive and gram negativebacteria including Staphylococcus, aureus, Proteus mirabilis,Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa,Streptococcus pyogenes, and against such fungi as Aspergillus niger,Candida albicans and Trichophyton mentagrophytes.

The actual determination of the numerical biological data definitive fora particular compound is readily determined by technicians versed inpharmacological test procedures, without the need for any extensiveexperimentation.

The compositions of this invention can be administered orally in theform of pills, tablets, capsules, e.g. in admixture with talc, starch,milk sugar or other inert, i.e. non-toxic or pharmacologicallyacceptable pharmaceutical carrier, or in the form of aqueous solutions,suspensions, encapsulated suspensions, gels, elixirs, aqueous alcoholicsolutions, e.g. in admixture with sugar or other sweetening agents,flavorings, colorants, thickeners and other conventional pharmaceuticalexcipients. When injected subcutaneously, intramuscularly orintravenously, usually the latter, they can be administered, e.g. as anaqueous or peanut oil solution or suspension using excipients andcarriers conventional for this mode of administration. The best route ofadministration and the best dosage will be apparent from the laboratorytests for activity and toxicity of the selected compound conventionallyundertaken as part of the development phase of a pharmaceutical.

The molecular structures of the compounds of the invention were assignedon the basis of the method of their preparation and study of their NMRspectra and confirmed by the correspondence between calculated and foundvalues for the elemental analyses of representative examples.

This invention is illustrated by the following examples without,however, being limited thereto.

EXAMPLE 1

A solution containing 6.0 g. of 6,7-dimethoxy-2-napthaleneethylaminehydrochloride in 150 ml. 48% hydrobromic acid was heated under reflux1.5 hours. The product, which precipitated upon cooling the reactionmixture, was collected by filtration. Additional product was obtained byevaporation of the filtrate in vacuo. The solids were combined andrecrystallized from 20% hydrochloric acid and then from water to yield3.3 g. of 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride, m.p.284°-286° C.

EXAMPLE 2

Following a procedure similar to that described in Example 1 but using16.0 g. of N-ethyl-6,7-dimethoxy-2-naphthaleneethylamine hydrochlorideand 200 ml. of 48% hydrobromic acid afforded 12.0 g. of6-[2-(ethylamino)ethyl]-2,3-naphthalenediol hydrochloride, m.p.225°-228° C.

EXAMPLE 3

Following a procedure similar to that described in Example 1 but using17.0 g. of 1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]pyrrolidinehydrochloride and 250 ml. of 48% hydrobromic acid provided 11.0 g. of6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol hydrochloride, m.p.227°-229° C.

EXAMPLE 4

Following a procedure similar to that described in Example 1 but using6,7-dimethoxy-N,N-dimethyl-2-naphthaleneethylamine hydrochlorideafforded 6-[2-(dimethylamino)ethyl]-2,3-naphthalenediol hydrochloride,m.p. 248°-250° C.

EXAMPLE 5

Following a procedure similar to that described in Example 1 but using14.5 g. of 6,7-dimethoxy-N-methyl-2-naphtaleneethylamine and 200 ml. of48% HBr afforded 10.0 g. of 6-[2-(methylamino)ethyl]-2,3-naphthalenediolhydrochloride, m.p. 215°-217° C.

EXAMPLE 6

Following a procedure similar to that in Example 1 but using 29.0 g. ofN,N-diethyl-6,7-dimethoxy-2-naphthaleneethylamine hydrochloride and 300ml. of 48% hydrobromic acid afforded6-[2-(diethylamino)ethyl]-2,3-naphthalenediol hydrochloride, m.p.195°-197° C. which was dissolved in hot water, cooled, and the aqueoussolution made basic with sodium bicarbonate. The resulting free base wascollected, washed with water and recrystallized from aqueous ethanol togive 7.7 g. of 6-[2-(diethylamino)ethyl]-2,3-naphthalenediol, m.p.125°-135° C.

EXAMPLE 7

A solution containing 10.1 g. of1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]-2-methylpiperidine hydrochloridein 300 ml. of concentrated hydrochloride acid was heated under reflux2.5 hours, filtered while still hot, and the filtrate cooled overnightat 5°-10° C. The precipitated product was collected and recrystallizedfrom methanol-ether to give 7.0 g. of6-[2-(2-methyl-1-piperidinyl)ethyl]-2,3-naphthalenediol hydrochloride,m.p. 234°-239° C.

EXAMPLE 8

Following a procedure similar to that in Example 7 but using 10.5 g. of1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]piperidine hydrochloride and 400ml. of concentrated hydrochloric acid afforded 7.0 g. of6-[2-(1-piperidinyl)ethyl]-2,3-naphthalenediol hydrochloride, m.p.293°-296° C.

EXAMPLE 9

Following a procedure similar to that in Example 7 but using 4.9 g. of1-[(6,7-dimethoxy-2-naphthyl)ethyl]hexamethyleneimine hydrochloride and140 ml. of concentrated hydrochloric acid yielded 3.8 g. of6-[2-(1-hexamethyleneiminyl)ethyl]-2,3-naphthalenediol hydrochloride,m.p. 284°-288° C. (dec.).

EXAMPLE 10

Following a procedure similar to that in Example 6 but using 9.7 g. ofN-phenyl-6,7-dimethoxy-2-naphthaleneethylamine hydrochloride and 150 ml.of 48% hydrobromic acid, provided 6-(2-anilinoethyl)-2,3-naphthalenediolwhich was dissolved in ethanol and treated with methanolic hydrogenchloride until acidic. Addition of ether effected precipitation of 2.3g. of 6-(2-anilinoethyl)-2,3-naphthalenediol hydrochloride, m.p.215°-218° C.

EXAMPLE 11

Following a procedure similar to that in Example 1 but using 8.8 g. of6,7-dimethoxy-α-methyl-2-naphthaleneethylamine hydrochloride and 50 ml.of 48% hydrobromic acid, there was obtained 6.3 g. of6-(2-aminopropyl)-2,3-naphthalenediol hydrochloride, m.p. 242°-245° C.

EXAMPLE 12

Following a procedure similar to that in Example 1 but using 5.3 g. of6,7-dimethoxy-β,β-dimethyl-2-naphthaleneethylamine hydrochloride and 75ml. of 48% hydrobromic acid, afforded 4.4 g. of6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol hydrochloride,m.p. >135° C. (dec.).

This compound showed significant antihypertensive activity whenadministered orally at three dose levels of 12.5, 25 and 50 mg./kg. toadrenal regeneration hypertensive rats prepared according to the methodsdescribed by F. R. Shelton, et al., Archives of Internal Medicine 98,449 (1956) and Circulation Research Supplement 1, Vols. 24 and 25, May1969 at pages I-35 through 56.

EXAMPLE 13

Following a procedure similar to that in Example 7 but using 5 g. of6,7-dimethoxy-1-naphthaleneethylamine and 200 ml. of concentratedhydrochloric acid yielded 4.8 g. of 5-(2-aminoethyl)-2,3-naphthalenediolhydrochloride, m.p. 95°-105° C.

EXAMPLE 14

Following a procedure similar to that in Example 7 but using 7.0 g. of6,7-dimethoxy-8-methyl-2-naphthaleneethylamine hydrochloride and 225 ml.of concentrated hydrochloric acid afforded 2.2 g. of6-(2-aminoethyl)-4-methyl-2,3-naphthalenediol hydrochloride, m.p.130°-160° C.

EXAMPLE 15

Following a procedure similar to that in Example 6 but using 10.0 g. of6,7-dimethoxy-2-naphthalenemethylamine and 150 ml. of 48% hydrobromicacid, there was obtained 3.6 g. of 6-(aminomethyl)-2,3-naphthalenediolhydrochloride, m.p. >300° C. (DMF).

EXAMPLE 16

Following a procedure similar to that in Example 7 but using 10.7 g. ofN-ethyl-6,7-dimethoxy-2-naphthalenemethylamine hydrochloride and 250 ml.of concentrated hydrochloric acid afforded 5.6 g. of6-[(ethylamino)methyl]-2,3-naphthalenediol hydrochloride, m.p. 246°-249°C.

EXAMPLE 17

Following a procedure similar to that in Example 7 but using 14.7 g. ofN,N-diethyl-6,7-dimethoxy-2-naphthalenemethylamine hydrochloride and 300ml. of concentrated hydrochloric acid there was obtained 9.2 g. of6-[(diethylamino)methyl]-2,3-naphthalenediol hydrochloride, m.p.192°-194° C.

EXAMPLE 18

Following a procedure similar to that in Example 7 but using 10.0 g. of1-[(6,7-dimethoxy-2-naphthyl)methyl]pyrrolidine hydrochloride and 300ml. of concentrated hydrochloric acid provided6-[(1-pyrrolidinyl)methyl]-2,3-naphthalenediol hydrochloride. Liberationof the free base as in Example 6 afforded 2.6 g. of6-[(1-pyrrolidinyl)methyl]-2,3-naphthalenediol, m.p. 114°-118° C.

EXAMPLE 19

Following a procedure similar to that in Example 1 but using 2.2 g. of6,7-dimethoxy-1-naphthalenemethylamine and 50 ml. of 48% hydrobromicacid, there was obtained 1.7 g. of 5-(aminoethyl)-2,3-naphthalenediolhydrochloride, m.p. 246°-248° C.

EXAMPLE 20

Following a procedure similar to that in Example 6 but using 9.0 g. of2-(tert-butylamino)-6',7'-dimethoxy-2'-acetonaphthone hydrochloride and100 ml. of 48% hydrobromic acid, yielded 2.5 g. of2-(tert-butylamino)-6',7'-dihydroxy-2'-acetonaphthone, m.p. >230° C.(dec.) (methanol).

EXAMPLE 21

Following a procedure similar to that in Example 1 but using 11.0 g. of2-(dimethylamino)-6',7'-dimethoxy-2'-acetonaphthone hydrochloride and200 ml. of 48% hydrobromic acid, there was obtained 5.6 g. of2-(dimethylamino)-6',7'-dihydroxy-2'-acetonaphthone hydrochloride, m.p.246°-250° C.

EXAMPLE 22

Following a procedure similar to that in Example 1 but using 38.5 g. of2-(benzylmethylamino)-6',7'-dimethoxy-2'-acetonaphthone and 500 ml. of48% hydrobromic acid yielded 31.0 g. of2-(benzylmethylamino)-6',7'-dihydroxy-2'-acetonaphtone hydrochloride,m.p. 229°-231° C.

EXAMPLE 23

Following a procedure similar to that in Example 1 but using 8.5 g. of2-(tert-butylamino)-6',7'-dimethoxy-1'-acetonaphthone and 250 ml. of 48%hydrobromic acid afforded 7.7 g. of2-(tert-butylamino)-6',7'-dihydroxy-1'-acetonaphthone hydrochloride,m.p. 248°-250° C. (dec.).

EXAMPLE 24

A solution containing 8.0 g. of 2-(tert-butylamino)-6',7'-dihydroxy-2'-acetonaphthone hydrochloride and 100 mg. of 10% palladium-on-carbon in100 ml. of dimethylformamide was shaken under a hydrogen pressure of20-50 psi for approximately six hours or until one molar equivalent ofhydrogen was absorbed. The catalyst was removed by filtration and thefiltrate was evaporated in vacuo. The residue was dissolved in water andthe aqueous solution made basic with sodium bicarbonate. The resultingprecipitate was collected and recrystallized fromdimethylformamide-ethanol to give 3.8 g. ofα-[(tert-butylamino)methyl]-6,7-dihydroxy-2-naphthalenemethanol,m.p. >300° C.

EXAMPLE 25

Following a procedure similar to that in Example 24 but using 7.8 g. of2-(tert-butylamino)-6',7'-dihydroxy-1'-acetonaphthone, there wasobtained 1.4 g. ofα-[(tert-butylamino)methyl]-6,7-dihydroxy-1-naphthalenemethanol hydrate,m.p. 140°-144° C.

EXAMPLE 26

A solution containing 30.0 g. of2-(benzylmethylamino)-6',7'-dihydroxy-2'-acetonaphthone and 300 mg. of10% palladium on carbon in 300 ml. of dimethylformamide was shaken undera hydrogen pressure of 20-50 psi until one molar equivalent of hydrogenwas absorbed. The reaction mixture was then warmed to 50° C. and afterapproximately six hours a second molar equivalent of hydrogen wasabsorbed. The catalyst was removed by filtration and the filtrate wasevaporated in vacuo. The residue was dissolved in water and the aqueoussolution made basic with sodium bicarbonate. The resulting precipitatewas collected and recrystallized from dimethylformamide to give 10.0 g.of 6,7-dihydroxy-α-[(methylamino)methyl]-2-naphthalenemethanol,m.p. >300° C.

EXAMPLE 27

A solution containing 6.8 g. of diethyl2-acetamido-2(6,7-dimethoxy-2-naphthylmethyl)malonate in 100 ml. ofacetic acid was heated under reflux while concentrated hydrochloric acidwas added dropwise at a rate sufficient to maintain a homogeneoussolution. After three hours, 250 ml. of acid had been added. The mixturewas heated under reflux an additional two hours, then cooled, dilutedwith 200 ml. of water and filtered to remove impurities. Evaporation ofthe filtrate in vacuo followed by trituration of the residue inacetonitrile for three hours afforded 3.0 g. of(6,7-dihydroxy-2-naphthyl)alanine hydrochloride, m.p. 242°-246° C.(dec.).

EXAMPLE 28

A suspension of 3.8 g. of 6,8-dimethoxy-1-naphthaleneethylaminehydrochloride in 6 N hydrochloric acid under nitrogen was heated to thereflux temperature over a period of 0.5 hours. Reflux was maintainedfive minutes and the reaction allowed to cool. The process was repeatedand the cooled mixture was then evaporated to dryness. The residue wasdissolved in ethanol and diluted with ether to give 3.0 g. of8-(2-aminoethyl)-1,3-naphthalenediol hydrochloride, m.p. 95°-105° C.

EXAMPLE 29

Following a procedure similar to that in Example 7 but using 6.0 g. ofN,N-diethyl-4,8-dimethoxy-1-naphthaleneethylamine hydrochloride and 100ml. of concentrated hydrochloric acid, there was obtained 2.7 g. of4-[2-(diethylamino)ethyl]-1,5-naphthalenediol hydrochloride, m.p.235°-237° C. (dec.).

EXAMPLE 30

Following a procedure similar to that in Example 7 but using 9.6 g. of1-[2-(4,8-dimethoxy-1-naphthyl)ethyl]pyrrolidine hydrochloride and 250ml. of concentrated hydrochloric acid, yielded 3.1 g. of4-[2-(1-pyrrolidinyl)ethyl]-1,5-naphthalenediol hydrochloride, m.p.216°-218° C. (dec.).

EXAMPLE 31

A solution containing 5.0 g. of 6-methoxy-2-naphthaleneethylaminehydrochloride in 50 ml. of 48% hydrobromic acid was heated on the steambath two hours followed by heating one hour under reflux. The reactionmixture was evaporated to dryness in vacuo and the residuerecrystallized from methanol-ether to give 3.8 g. of6-(2-aminoethyl)-2-naphthol hydrobromide, m.p. 289°-291° C.

EXAMPLE 32

Following a procedure similar to that in Example 31 but using 8.5 g. ofN-ethyl-6-methoxy-2-naphthaleneethylamine hydrochloride and 64 ml. of48% hydrobromic acid, there was obtained 6.7 g. of6-[2-(ethylamino)ethyl]-2-naphthol hydrobromide, m.p. 227°-228° C.

EXAMPLE 33

Following a procedure similar to that in Example 31 but using 7.0 g. of1-[2-(6-methoxy-2-naphthyl)ethyl]pyrrolidine hydrochloride and 28 ml. of48% hydrobromic acid, yielded 6.5 g. of6-[2-(1-pyrrolidinyl)ethyl]-2-naphthol hydrobromide, m.p. 207°-208.5° C.

EXAMPLE 34

Following a procedure similar to that in Example 31 but using 5.0 g. of6-methoxy-β-methyl-2-naphthaleneethylamine hydrochloride and 35 ml. of48% hydrobromic acid, afforded 4.9 g. of6-(2-amino-1-methylethyl)-2-naphthol hydrobromide, m.p. 236°-236.5° C.

EXAMPLE 35

Following a procedure similar to that described in Example 31 but using7.0 g. of 1-[2-(6-methoxy-2-naphthyl)propyl]pyrrolidine hydrochlorideand 30 ml. of 48% hydrobromic acid, there was obtained 2.1 g. of6-[1-methyl-2-(1-pyrrolidinyl)ethyl]-2-naphthol hydrobromide, m.p.189°-191° C.

EXAMPLE 36

A 1.1-gram sample of 7-methoxy-2-naphthaleneethylamine hydrochloride wasadded portionwise to 20 ml. of refluxing 48% hydrobromic acid. Whenaddition was complete the mixture was heated under reflux for one hour.Upon cooling the product precipitated. The product was collected,combined with another batch prepared from 3.1 g. of7-methoxy-2-naphthaleneethylamine hydrochloride and recrystallized frommethanol-ether to give 2.7 g. of 7-(2-aminoethyl)-2-naphtholhydrobromide, m.p. 237°-237.5° C.

EXAMPLE 37

Following a procedure similar to that in Example 36 but using 5.0 g. ofN-(1-methyl-3-phenylpropyl)-6,7-dimethoxy-2-naphthaleneethylaminehydrochloride and 40 ml. of 48% hydrobromic acid, there was obtained 4.1g. of 6-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2,3-naphthalenediolhydrobromide, m.p. 182° C.

EXAMPLE 38

Following a procedure similar to that in Example 31 but using 7.0 g. ofN-[3-(p-methoxyphenyl)-1-methylpropyl]-6,7-dimethoxy-2-naphthaleneethylaminehydrochloride and 105 ml. of 48% hydrobromic acid provided 5.4 g. of6-<2-{[3-(p-hydroxyphenyl)-1-methylpropyl]amino}ethyl>-2,3-naphthalenediolhydrobromide, m.p. 232°-232.5° C.

EXAMPLE 39

To a stirred solution containing 5.0 g. of6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride in 70 ml. oftrifluoroacetic acid at 0° C. was added dropwise 8.0 g. of acetylchloride. When the addition was complete the mixture was stirred at 0°C. three hours and then at room temperature one hour. The reactionmixture was then diluted with 80 ml. of water and stirred an additionalhour at room temperature. Following evaporation of the reaction mixturein vacuo the residue was allowed to crystallize slowly overnight.Recrystallization from 2-propanol afforded 3.0 g. of6-(2-aminoethyl)-2,3-naphthalenediol diacetate hydrochloride, m.p.181°-183° C.

By following a procedure similar to that described in Example 39 butsubstituting for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(methylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(ethylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(dimethylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(diethylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-(2-anilinoethyl)-2,3-naphthalenediol hydrochloride;

6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-(2-aminoethyl)-4-methyl-2,3-naphthalenediol hydrochloride;

5-(2-aminoethyl)-2,3-naphthalenediol hydrochloride;

5-(2-aminoethyl)-4-methyl-2,3-naphthalenediol hydrochloride;

5-(2-aminopropyl)-2,3-naphthalenediol hydrochloride;

6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol hydrochloride;

6-[2-(ethylamino)-1,1-dimethylethyl]-2,3-naphthalenediol hydrochloride;

6-(2-amino-1,1-dimethylethyl)-4-methyl-2,3-naphthalenediolhydrochloride;

5-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol hydrochloride;

6-(aminomethyl)-2,3-naphthalenediol hydrochloride;

6-[(benzylamino)methyl]-2,3-naphthalenediol hydrochloride;

2-(dimethylamino)-6',7'-dihydroxy-2'-acetonaphthone hydrochloride;

2-(benzylmethylamino)-6',7'-dihydroxy-2'-acetonaphthone hydrochloride;

6',7'-dihydroxy-2-(1-pyrrolidinyl)-1'-acetonaphthone hydrochloride;

6',7'-dihydroxy-8'-methyl-2-(1-pyrrolidinyl)-2'-propionaphthonehydrochloride;

(6,7-dihydroxy-2-naphthyl)alanine hydrochloride;

8-(2-aminoethyl)-1,3-naphthalenediol hydrochloride;

8-{2-[4-(2,6-dimethylmorpholinyl)]ethyl}-1,3-naphthalenediolhydrochloride;

7-(2-aminoethyl)-1,3-naphthalenediol hydrochloride;

5-(2-aminoethyl)-1,2-naphthalenediol hydrochloride;

6-(2-aminoethyl)-1,2-naphthalenediol hydrochloride;

4-[2-(diethylamino)ethyl]-1,5-naphthalenediol hydrochloride, and

4-(2-aminopropyl)-1,5-naphthalenediol hydrochloride; there are obtainedrespectively:

6-[2-(methylamino)ethyl]-2,3-naphthalenediol diacetate hydrochloride;

6-[2-(ethylamino)ethyl]-2,3-naphthalenediol diacetate hydrochloride;

6-[2-(dimethylamino)ethyl]-2,3-naphthalenediol diacetate hydrochloride;

6-[2-(diethylamino)ethyl]-2,3-naphthalenediol diacetate hydrochloride;

6-(2-anilinoethyl)-2,3-naphthalenediol diacetate hydrochloride;

6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol diacetate hydrochloride;

6-(2-aminoethyl)-4-methyl-2,3-naphthalenediol diacetate hydrochloride;

5-(2-aminoethyl)-2,3-naphthalenediol diacetate hydrochloride;

5-(2-aminoethyl)-4-methyl-2,3-naphthalenediol diacetate hydrochloride;

5-(2-aminopropyl)-2,3-naphthalenediol diacetate hydrochloride;

6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol diacetatehydrochloride;

6-[2-(ethylamino)-1,1-dimethylethyl]-2,3-naphthalenediol diacetatehydrochloride;

6-(2-amino-1,1-dimethylethyl)-4-methyl-2,3-naphthalenediol diacetatehydrochloride;

5-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol diacetatehydrochloride;

6-(aminomethyl)-2,3-naphthalenediol diacetate hydrochloride;

6-[(benzylamino)methyl]-2,3-naphthalenediol diacetate hydrochloride;

6',7'-diacetoxy-2-(dimethylamino)-2'-acetonaphthone hydrochloride;

6',7'-diacetoxy-2-(benzylmethylamino)-2'-acetonaphthone hydrochloride;

6',7'-diacetoxy-2-(1-pyrrolidinyl)-1'-acetonaphthone hydrochloride;

6',7'-diacetoxy-8'-methyl-2-(1-pyrrolidinyl)-2'-propionaphthonehydrochloride;

(6,7-diacetoxy-2-naphthyl)alanine hydrochloride;

8-(2-aminoethyl)-1,3-naphthalenediol diacetate hydrochloride;

8-{2-[4-(2,6-dimethylmorpholinyl)]ethyl}-1,3-naphthalenediol diacetatehydrochloride;

7-(2-aminoethyl)-1,3-naphthalenediol diacetate hydrochloride;

5-(2-aminoethyl)-1,2-naphthalenediol diacetate hydrochloride;

6-(2-aminoethyl)-1,2-naphthalenediol diacetate hydrochloride;

4-[2-(diethylamino)ethyl]-1,5-naphthalenediol diacetate hydrochloride,and

4-(2-aminopropyl)-1,5-naphthalenediol diacetate hydrochloride.

By following a procedure similar to that described in Example 39 butsubstituting for acetyl chloride an equivalent amount of acetyl bromideand for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride an equivalentamount of the following:

6-(2-aminoethyl)-2-naphthol hydrobromide;

6-[2-(benzylamino)ethyl]-2-naphthol hydrobromide;

6-(2-aminopropyl)-2-naphthol hydrobromide;

6-(2-amino-1-methylethyl)-2-naphthol hydrobromide; and

6-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2,3-naphthalenediolhydrobromide;

there are obtained respectively:

6-(2-aminoethyl)-2-naphthol acetate hydrobromide;

6-[2-(benzylamino)ethyl]-2-naphthol acetate hydrobromide;

6-(2-aminopropyl)-2-naphthol acetate hydrobromide;

6-(2-amino-1-methylethyl)-2-naphthol acetate hydrobromide, and

6-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2,3-naphthalenedioldiacetate hydrobromide.

By following a procedure similar to that described in Example 39 butsubstituting for acetyl chloride an equivalent amount of propionylchloride, and for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(1-piperidinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(2-methyl-1-piperidinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(1-hexamethyleneiminyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(isopropylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(ethylamino)propyl]-4-methyl-2,3-naphthalenediol hydrochloride;

5-[2-(1-pyrrolidinyl)propyl]-4-methyl-2,3-naphthalenediol hydrochloride;

5-[2-(ethylamino)-1,1-dimethylethyl]-2,3-naphthalenediol hydrochloride;

6-[(ethylamino)methyl]-2,3-naphthalenediol hydrochloride;

6-aminomethyl-4-methyl-2,3-naphthalenediol hydrochloride;

2-amino-6',7'-dihydroxy-2'-acetonaphthone hydrochloride;

2-(tert-butylamino)-6',7'-dihydroxy-1'-acetonaphthone hydrochloride;

(6,7-dihydroxyl-1-naphthyl)alanine hydrochloride;

8-[2-(ethylamino)ethyl]-1,3-naphthalenediol hydrochloride;

8-(2-amino-1,1-dimethylethyl)-1,3-naphthalenediol hydrochloride;

6-[2-(ethylamino)ethyl]-1,2-naphthalenediol hydrochloride, and

4-[2-(1-pyrrolidinyl)ethyl]-1,5-naphthalenediol hydrochloride;

there are obtained respectively:

6-[2-(1-piperidinyl)ethyl]-2,3-naphthalenediol dipropionatehydrochloride;

6-[2-(2-methyl-1-piperidinyl)ethyl]-2,3-naphthalenediol dipropionatehydrochloride;

6-[2-(1-hexamethyleneiminyl)ethyl]-2,3-naphthalenediol dipropionatehydrochloride;

6-[2-(isopropylamino)ethyl]-2,3-naphthalenediol dipropionatehydrochloride;

6-[2-(ethylamino)propyl]-4-methyl-2,3-naphthalenediol hydrochloride;

5-[2-(1-pyrrolidinyl)propyl]-4-methyl-2,3-naphthalenediol dipropionatehydrochloride;

5-[2-(ethylamino)-1,1-dimethylethyl]-2,3-naphthalenediol dipropionatehydrochloride;

6-[(ethylamino)methyl]-2,3-naphthalenediol dipropionate hydrochloride;

6-aminomethyl-4-methyl-2,3-naphthalenediol dipropionate hydrochloride;

2-amino-6',7'-dipropionyloxy-2'-acetonaphthone hydrochloride;

2-(tert-butylamino)-6',7'-dipropionyloxy-1'-acetonaphthonehydrochloride;

(6,7-dipropionyloxy-1-naphthyl)alanine hydrochloride;

8-[2-(ethylamino)ethyl]-1,3-naphthalenediol dipropionate hydrochloride;

8-(2-amino-1,1-dimethylethyl)-1,3-naphthalenediol dipropionatehydrochloride;

6-[2-(ethylamino)ethyl]-1,2-naphthalenediol dipropionate hydrochloride,and

4-[2-(1-pyrrolidinyl)ethyl]-1,5-naphthalenediol dipropionatehydrochloride.

By following a procedure similar to that described in Example 39 butsubstituting for acetyl chloride an equivalent amount of propionylbromide, and for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(methylamino)ethyl]-2-naphthol hydrobromide;

6-(2-anilinoethyl)-2-naphthol hydrobromide;

7-(2-amino-1-methylethyl)-2-naphthol hydrobromide, and

6-{[2-(1-methyl-3-phenylpropyl)amino]ethyl}-2-naphthol hydrobromide;

there are obtained respectively:

6-[2-(methylamino)ethyl]-2-naphthol propionate hydrobromide;

6-(2-anilinoethyl)-2-naphthol propionate hydrobromide;

7-(2-amino-1-methylethyl)-2-naphthol propionate hydrobromide, and

6-{[2-(1-methyl-3-phenylpropyl)amino]ethyl}-2-naphthol propionatehydrobromide.

EXAMPLE 40

To a stirred suspension of 4.0 g. of6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride in 50 ml. oftrifluoroacetic acid at 0° C. was added dropwise 10.5 g. of p-toluylchloride. When the addition was complete the mixture was stirred onehour at 0° C. and then two hours at room temperature. The reactionmixture was then diluted with 50 ml. of water and stirred an additionaltwo hours at room temperature. Following evaporation of the reactionmixture in vacuo, the residue was partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate. After separating the layers, theaqueous portion was re-extracted with ethyl acetate. The combinedorganic extracts were washed with water, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The residue was dissolved in methanoland treated with methanolic hydrogen chloride until acidic. Addition ofether and cooling precipitated the salt. Two recrystallizations fromethanol-ether afforded 2.2 g. of 6-(2-aminoethyl)-2,3-naphthalenedioldi-p-toluate hydrochloride, m.p. 188°-190° C.

By following a procedure similar to that described in Example 40 butsubstituting for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(4-morpholinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(benzylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-{2-[4-(2,6-dimethylmorpholinyl)]ethyl}-2,3-naphthalenediolhydrochloride;

6-(2-aminopropyl)-2,3-naphthalenediol hydrochloride;

6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol hydrochloride;

5-(aminomethyl)-2,3-naphthalenediol hydrochloride;

2-(ethylamino)-6',7'-dihydroxy-8'-methyl-1'-acetonaphthonehydrochloride;

2-amino-6',7'-dihydroxy-1'-propionaphthone hydrochloride;

6',7'-dihydroxy-8'-methyl-2-(1-pyrrolidinyl)-1'-propionaphthonehydrochloride;

(6,7-dihydroxy-1-naphthyl)alanine hydrochloride;

8-[2-(1-piperidinyl)ethyl]-1,3-naphthalenediol hydrochloride;

5-[2-(1-hexamethyleneiminyl)ethyl]-1,2-naphthalenediol hydrochloride;

6-[2-(1-pyrrolidinyl)-1,1-dimethylethyl]-1,2-naphthalenediolhydrochloride;

4-(2-anilinoethyl)-1,5-naphthalenediol hydrochloride, and

4-[2-(1-pyrrolidinyl)propyl]-1,5-naphthalenediol hydrochloride;

there are obtained respectively:

6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol di-p-toluatehydrochloride;

6-[2-(4-morpholinyl)ethyl]-2,3-naphthalenediol di-p-toluatehydrochloride;

6-[2-(benzylamino)ethyl]-2,3-naphthalenediol di-p-toluate hydrochloride;

6-{2-[4-(2,6-dimethylmorpholinyl)]ethyl}-2,3-naphthalenedioldi-p-toluate hydrochloride;

6-(2-aminopropyl)-2,3-naphthalenediol di-p-toluate hydrochloride;

6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol di-p-toluatehydrochloride;

5-(aminomethyl)-2,3-naphthalenediol di-p-toluate hydrochloride;

2-(ethylamino)-8'-methyl-6',7'-di-p-toluyloxy-1'-acetonaphthonehydrochloride;

2-amino-6',7'-di-p-toluyloxy-1'-propionaphthone hydrochloride;

8'-methyl-2-(1-pyrrolidinyl)-6',7'-di-p-toluyloxy-1'-propionaphthonehydrochloride;

(6,7-di-p-toluyloxy-1-naphthyl)alanine hydrochloride;

8-[2-(1-piperidinyl)ethyl]-1,3-naphthalenediol di-p-toluatehydrochloride;

5-[2-(1-hexamethyleneiminyl)ethyl]-1,2-naphthalenediol di-p-toluatehydrochloride;

6-[2-(1-pyrrolidinyl)-1,1-dimethylethyl]-1,2-naphthalenedioldi-p-toluate hydrochloride;

4-(2-anilinoethyl)-1,5-naphthalenediol di-p-toluate hydrochloride, and

4-[2-(1-pyrrolidinyl)propyl]-1,5-naphthalenediol di-p-toluatehydrochloride.

By following a procedure similar to that described in Example 40 butsubstituting for p-toluyl chloride an equivalent amount of p-toluylbromide and for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(1-pyrrolidinyl)ethyl]-2-naphthol hydrobromide;

6-[2-n-butylamino)ethyl]-2-naphthol hydrobromide;

7-(2-aminoethyl)-2-naphthol hydrobromide;

7-(2-amino-1,1-dimethylethyl)-2-naphthol hydrobromide, and

6-<2-{[3-(p-methoxyphenyl)-1-methylpropyl]amino}ethyl>-2,3-naphthalenediolhydrobromide;

there are obtained respectively:

6-[2-(1-pyrrolidinyl)ethyl]-2-naphthol p-toluate hydrobromide;

6-[2-(n-butylamino)ethyl]-2-naphthol p-toluate hydrobromide;7-(2-aminoethyl)-2-naphthol p-toluate hydrobromide;

7-(2-amino-1,1-dimethylethyl)-2-naphthol p-toluate hydrobromide, and

6-<2-{[3-(p-methoxyphenyl)-1-methylpropyl]amino}ethyl>-2,3-naphthalenedioldi-p-toluate hydrobromide.

By following a procedure similar to that described in Example 40 butsubstituting for p-toluyl chloride an equivalent amount of benzoylchloride and for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(ethylamino)ethyl]-4-methyl-2,3-naphthalenediol hydrochloride;

6-[2-(1-pyrrolidinyl)ethyl]-4-methyl-2,3-naphthalenediol hydrochloride;

5-[2-(1-pyrrolidinyl)-1-methylethyl]-2,3-naphthalenediol hydrochloride;

6-[(tert-butylamino)methyl]-2,3-naphthalenediol hydrochloride;

6',7'-dihydroxy-8'-methyl-2-(1-pyrrolidinyl)-2'-acetonaphthonehydrochloride;

8-[2-(1-pyrrolidinyl)ethyl]-1,3-naphthalenediol hydrochloride;

7-(2-amino-1-methylethyl)-1,3-naphthalenediol hydrochloride;

5-(2-amino-1,1-dimethylethyl)-1,2-naphthalenediol hydrochloride, and

4-[2-(1-piperidinyl)ethyl]-1,5-naphthalenediol hydrochloride;

there are obtained respectively:

6-[2-(ethylamino)ethyl]-4-methyl-2,3-naphthalenediol dibenzoatehydrochloride;

6-[2-(1-pyrrolidinyl)ethyl]-4-methyl-2,3-naphthalenediol dibenzoatehydrochloride;

5-[2-(1-pyrrolidinyl)-1-methylethyl]-2,3-naphthalenediol dibenzoatehydrochloride;

6-[(tert-butylamino)methyl]-2,3-naphthalenediol dibenzoatehydrochloride;

6',7'-dibenzoyloxy-8'-methyl-2-(1-pyrrolidinyl)-2'-acetonaphthonehydrochloride;

8-[2-(1-pyrrolidinyl)ethyl]-1,3-naphthalenediol dibenzoatehydrochloride;

7-(2amino-1-methylethyl)-1,3-naphthalenediol dibenzoate hydrochloride;

5-(2-amino-1,1-dimethylethyl)-1,2-naphthalenediol dibenzoatehydrochloride, and

4-[2-(1-piperidinyl)ethyl]-1,5-naphthalenediol hydrochloride.

By following a procedure similar to that described in Example 40 butsubstituting for p-toluyl chloride an equivalent amount of benzoylbromide, and for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(isopropylamino)ethyl]-2-naphthol hydrobromide;

6-[2-(1-pyrrolidinyl)-1,1-dimethylethyl]-2-naphthol hydrobromide, and

7-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2-naphthol hydrobromide;

there are obtained respectively:

6-[2-(isopropylamino)ethyl]-2-naphthol benzoate hydrobromide;

6-[2-(1-pyrrolidinyl)-1,1-dimethylethyl]-2-naphthol benzoatehydrobromide, and

7-{2-[(1-methyl-3-phenylpropyl)amino]ethyl}-2-naphthol benzoatehydrobromide.

EXAMPLE 41

A solution containing 6.0 g. of 6-(2-aminoethyl)-2,3-naphthalenediolhydrochloride and 16 g. of isobutyryl chloride in 75 ml. oftrifluoroacetic acid was heated under reflux overnight. The cooledreaction mixture was diluted with 200 ml. of water and stirred at roomtemperature two hours. Following evaporation of the solvents in vacuothe residue was triturated with chloroform and a chloroform-insolublematerial was removed by filtration. Addition of ether to the filtrateprecipitated the desired product which was recrystallized fromchloroform-n-hexane to give 2.6 g. of6-(2-aminoethyl)-2,3-naphthalenediol diisobutyrate hydrochloride, m.p.135°-138° C.

By following a procedure similar to that described in Example 41 butsubstituting for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(ethylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(tert-butylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(ethylmethylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[2-(n-butylamino)ethyl]-2,3-naphthalenediol hydrochloride;

4-methyl-6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol hydrochloride;

6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol hydrochloride;

5-(2-amino-1-methylethyl)-4-methyl-2,3-naphthalenediol hydrochloride;

6-[(dimethylamino)methyl]-2,3-naphthalenediol hydrochloride;

6-(2-methylpiperidinyl)methyl-2,3-naphthalenediol hydrochloride;

5-(ethylaminomethyl)-4-methyl-2,3-naphthalenediol hydrochloride;

2-(tert-butylamino)-6',7'-dihydroxy-2'-acetonaphthone hydrochloride;

6',7'-dihydroxy-2-(1-pyrrolidinyl)-2'-acetonaphthone hydrochloride;

2-anilino-6',7'-dihydroxy-2'-acetonaphthone hydrochloride;

2-amino-6',7'-dihydroxy-1-propionaphthone hydrochloride;

(6,7-dihydroxy-2-naphthyl)alanine hydrochloride;

5-[2-(isopropylamino)ethyl]-1,2-naphthalenediol hydrochloride, and

5-(2-aminoethyl)-1,5-naphthalenediol hydrochloride;

there are obtained respectively:

6-[2-(ethylamino)ethyl]-2,3-naphthalenediol diisobutyrate hydrochloride;

6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol diisobutyratehydrochloride;

6-[2-(tert-butylamino)ethyl]-2,3-naphthalenediol diisobutyratehydrochloride;

6-[2-(ethylmethylamino)ethyl]-2,3-naphthalenediol diisobutyratehydrochloride;

6-[2-(n-butylamino)ethyl]-2,3-naphthalenediol diisobutyratehydrochloride;

4-methyl-6-[2-(1-pyrrolidinyl)ethyl]-2,3-naphthalenediol diisobutyratehydrochloride;

6-(2-amino-1,1-dimethylethyl)-2,3-naphthalenediol diisobutyratehydrochloride;

5-(2-amino-1-methylethyl)-4-methyl-2,3-naphthalenediol diisobutyratehydrochloride;

6-[(dimethylamino)methyl]-2,3-naphthalenediol diisobutyratehydrochloride;

6-(2-methylpiperidinyl)methyl-2,3-naphthalenediol diisobutyratehydrochloride;

5-[(ethylamino)methyl]-4-methyl-2,3-napthalenediol diisobutyratehydrochloride;

2-(tert-butylamino)-6',7'-diisobutyryloxy-2'-acetonphathonehydrochloride;

6',7'-diisobutyryloxy-2-(1-pyrrolidinyl)-2'-acetonaphthonehydrochloride;

2-anilino-6',7'-diisobutyryloxy-2'-acetonaphthone hydrochloride;

2-amino-6',7'-diisobutyryloxy-1'-propionaphthone hydrochloride;

(6,7-diisobutyryloxy-2-naphthyl)alanine hydrochloride;

5-[2-(isopropylamino)ethyl]-1,2-naphthalenediol diisobutyratehydrochloride, and

5-(2-aminoethyl)-1,5-naphthalenediol diisobutyrate hydrochloride.

By following a procedure similar to that described in Example 41 butsubstituting for isobutyryl chloride an equivalent amount of isobutyrylbromide, and for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(ethylamino)ethyl]-2-naphthol hydrobromide;

6-[2-(1-hexamethyleneiminyl)ethyl]-2-naphthol hydrobromide;

6-[2-(1-pyrrolidinyl)-1-methylethyl]-2-naphthol hydrobromide;

7-[2-(1-pyrrolidinyl)propyl]-2-naphthol hydrobromide, and

6-<2-Δ[3-(p-hydroxyphenyl)-1-methylpropyl]amino}ethyl>-2,3-naphthalenediolhydrobromide;

there are obtained respectively:

6-[2-(ethylamino)-ethyl]-2-naphthol isobutyrate hydrobromide;

6-[2-(1-hexamethyleneiminyl)ethyl]-2-naphthol isobutyrate hydrobromide;

6-[2-(1-pyrrolidinyl)-1-methylethyl]-2-naphthol isobutyratehydrobromide;

7-[2-(1-pyrrolidinyl)propyl]-2-naphthol isobutyrate hydrobromide, and

6-<2-{[3-(p-isobutyryloxyphenyl)-1-methylpropyl]amino}ethyl>-2,3-naphthalenedioldiisobutyrate hydrobromide.

EXAMPLE 42

To a stirred mixture of 6.0 g. of 6-(2-aminoethyl)-2,3-naphthalenediolhydrochloride and 75 ml. of trifluoroacetic acid at 0° C. was addeddropwise 11.0 g. of isobutyryl chloride. When the addition was completethe mixture was stirred three hours at 0° C. and then at roomtemperature overnight. The reaction was then diluted with 150 ml. ofwater and stirred an additional two hours. The resulting oily salt wasdrawn off, dissolved in methanolic hydrogen chloride and precipitatedwith ether. Remaining traces of water were driven off by dissolving theproduct in methanol adding benzene and evaporating to dryness in vacuo.Recrystallization from 2-propanol-ether afforded 5.5 g. of6-(2-aminoethyl)-2,3-naphthalenediol 3(or 2)-isobutyrate hydrochloride,m.p. 250°-260° C. (with sintering at 200° C.)

By following a procedure similar to that described in Example 42 butsubstituting for 6-(2-aminoethyl)-2,3-naphthalenediol hydrochloride anequivalent amount of the following:

6-[2-(ethylamino)ethyl]-2,3-naphthalenediol hydrochloride;

6-[(1-pyrrolidinyl)methyl]-2,3-naphthalenediol hydrochloride;

2-(ethylamino)-6',7'-dihydroxy-2'-acetonaphthone hydrochloride;

8-[2-(diethylamino)ethyl]-1,3-naphthalenediol hydrochloride;

5-[2-(1-pyrrolidinyl)ethyl]-1,2-naphthalenediol hydrochloride; and

4-[2-(ethylamino)ethyl]-1,5-naphthalenediol hydrochloride;

there are obtained respectively:

6-[2-(ethylamino)ethyl]-2,3-naphthalenediol 2(or 39-isobutyratehydrochloride;

6-[(1-pyrrolidinyl)methyl]-2,3-naphthalenediol 2(or 3)-isobutyratehydrochloride;

2-(ethylamino)-6'(or 7')-hydroxy-7'(or6')-isobutyryloxy-2'-acetonaphthone hydrochloride;

8-[2-(diethylamino)ethyl]-1,3-naphthalenediol 3(or 1)-isobutyratehydrochloride;

5-[2-(1-pyrrolidinyl)ethyl]-1,2-naphthalenediol 1(or 2)-isobutyratehydrochloride; and

4-[2-(ethylamino)ethyl]-1,5-naphthalenediol 1(or 5)-isobutyratehydrochloride.

EXAMPLE 43

A mixture containing 7.0 g. of6',7'-dimethoxy-2-(dimethylamino)-2'-acetonaphthone hydrochloride, 80ml. of acetic acid, 10 ml. of water, 10 ml. of concentratedhydrochloride acid, and 1.0 g. of 10% palladium-on-carbon was shakenunder a hydrogen pressure of 10-50 psi at 40°-50° C. until twoequivalents of hydrogen were absorbed (approximately seven hours). Thecatalyst was removed by filtration and the filtrate was evaporated todryness in vacuo. The residue was partitioned between chloroform anddilute aqueous sodium hydroxide. The chloroform extracts were dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. The residuewas dissolved in 2-propanol and treated with methanolic hydrogenchloride until acidic. Evaporation to dryness in vacuo left a solidwhich was recrystallized twice from methanolether to give 4.5 g. of6,7-dimethoxy-N,N-dimethyl-2-naphthaleneethylamine hydrochloride, m.p.222°-223° C. (dec.).

EXAMPLE 44

Following a procedure similar to that in Example 43 but using 7.2 g. of2-(tert-butylamino)-6',7'-dimethoxy-2'-acetonaphthone, there wereobtained 3.9 g. of N-(tert-butyl)-6,7-dimethoxy-2-naphthaleneetheylaminehydrochloride, m.p. 250°-251° C. (dec.).

EXAMPLE 45

A solution containing 27 g. of6',7'-dimethoxy-2-(1-pyrrolidino)-2'-acetonaphthone hydrochloride in 300ml. of 20% aqueous hydrochloric acid was shaken at 55° C. overnightunder a hydrogen pressure of 20-50 psi in the presence of 300 mg. of 10%palladium-on-carbon. Two molar equivalents of hydrogen were absorbed.The catalyst was removed by filtration and the filtrate was evaporatedto dryness in vacuo. Recrystallization of the residue from ethanol-etherafforded the hydrochloride as a hydroscopic solid. A 10.0-gram sample ofthe salt was partitioned between ether and dilute aqueous sodiumhydroxide. The ethereal extracts were washed successively with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand evaporated to dryness in vacuo. The residue was recrystallized fromaqueous methanol to give 5.0 g. of1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]-pyrrolidine, m.p. 94°-96° C.

EXAMPLE 46

A solution containing 112 g. of2-(N,N-dibenzylamino)-6',7'-dimethoxy-2'-acetonaphthone in 1.1 liters ofdimethylformamide was shaken at 40°-50° C. under a hydrogen pressure of20-50 psi in the presence of 10.0 g. of 10% palladium-on-carbon. Afterthe absorption of three molar equivalents of hydrogen the catalyst wasremoved by filtration and the filtrate was evaporated to dryness invacuo. The residue was dissolved in 1.2 liters of 2 N hydrochloric acidand hydrogenated overnight at 60°-64° C. in the presence of 10.0 g. of10% palladium-on-carbon. The hydrogenation mixture was filtered warm andupon cooling the filtrate the product precipitated. Recrystallizationfrom 95% ethanol afforded 39 g. of 6,7-dimethoxy-2-naphthaleneethylaminehydrochloride, m.p. 249°-250° C.

EXAMPLE 47

A solution containing 7.0 g. of6-(2-chloroethyl)-2,3-dimethoxynaphthalene in 100 ml. ofdimethylformamide was added dropwise to 100 ml. of stirred diethylamineat 0°-5° C. When the addition was complete the reaction mixture wasallowed to come to room temperature and stirred overnight. After heatingunder reflux six hours the reaction mixture was evaporated to dryness invacuo. The residue was partitioned between ether and water. The etherealextracts were washed successively with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and acidifiedwith methanolic hydrogen chloride. The precipitated product wascollected and the filtrate was evaporated to dryness in vacuo. Theresidue was again subjected to the above reaction conditions using 50ml. of dimethylformamide and 50 ml. of diethylamine and a reflux periodof two days. The products were combined and recrystallized fromethanol-ether to give 4.0 g. ofN,N-diethyl-6,7-dimethoxy-2-naphthaleneethylamine hydrochloride, m.p.195°-197° C.

EXAMPLE 48

To a suspension of 10.0 g. ofN-methyl-6,7-dimethoxy-2-naphthaleneacetamide in 350 ml. oftetrahydrofuran at 0°-5° C. was added dropwise 140 ml. of a 1 M solutionof borane in tetrahydrofuran. When the addition was complete thereaction mixture was stirred at 0°-5° C. for two hours, then at roomtemperature overnight and finally at the reflux temperature for sixhours. The ice-cooled reaction mixture was then treated dropwise with 40ml. of ethanol and the resulting solution acidified with ethanolichydrogen chloride and kept cold two hours. The product was collected andrecrystallized twice from methanol-ether to give 6.2 g. of6,7-dimethoxy-N-methyl-2-naphthaleneethylamine hydrochloride, m.p.230°-231° C.

EXAMPLE 49

Following a procedure similar to that in Example 48 but using 5.0 g. ofN-ethyl-6,7-dimethoxy-2-naphthaleneacetamide and 60 ml. of a 1 Msolution of borane in tetrahydrofuran, there was obtained 3.5 g. of thehydrochloride which was partitioned between ether and aqueousdiethylamine. Evaporation of the ether provided the free base which wasredissolved in ether and acidified with methanolic hydrogen chloride toprecipitate 2.6 g. of N-ethyl-6,7-dimethoxy-2-naphthaleneethylaminehydrochloride, m.p. 239°-241° C.

EXAMPLE 50

Following a procedure similar to that in Example 48 but using 8.0 g. of1-(6,7-dimethoxy-2-naphthylacetyl)piperidine and 120 ml. of a 1 Msolution of borane in tetrahydrofuran, there was obtained 6.4 g. of1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]piperidine hydrochloride, m.p.246°-247° C. (dec.).

EXAMPLE 51

Following a procedure similar to that in Example 48 but using 32.9 g. of1-(6,7-dimethoxy-2-naphthylacetyl)-2-methylpiperidine and 300 ml. of a 1M solution of borane in tetrahydrofuran, afforded 17.8 g. of1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]-2-methylpiperidine hydrochloride,m.p. 216°-227° C. (dec.).

EXAMPLE 52

Following a procedure similar to that in Example 48 but using 16.5 g. of1-(6,7-dimethoxy-2-naphthylacetyl)hexamethyleneimine and 150 ml. of a 1M solution of borane in tetrahydrofuran afforded the hydrochloride whichwas warmed on the steam bath 2.5 hours in 15% aqueous sulfuric acid. Thecooled solution was made alkaline with dilute potassium hydroxide. Theprecipitated free base was collected, dissolved in benzene, and thebenzene-insoluble inorganic material was separated. The benzene wasevaporated and the residue was recrystallized from aqueous methanol. Thepurified free base was then dissolved in ethanol and acidified withmethanolic hydrogen chloride. The addition of ether precipitated 9.1 g.of 1-[6,7-dimethoxy-2-naphthyl)ethyl]hexamethyleneimine hydrochloride,m.p. 255°-261° C. (dec.).

EXAMPLE 53

Following a procedure similar to that in Example 48 but using 9.0 g. of4-(6,7-dimethoxy-2-naphthylacetyl)morpholine and 120 ml. of a 1 Msolution of borane in tetrahydrofuran, there was obtained 7.5 g. of4-[2-(6,7-dimethoxy-2-naphthyl)ethyl]morpholine hydrochloride, m.p.237°-238° C. (dec.).

EXAMPLE 54

Following a procedure similar to that in Example 52 but using 9.0 g. of6,7-dimethoxy-N-phenyl-2-naphthaleneacetamide and 110 ml. of a 1 Msolution of borane in tetrahydrofuran afforded 2.9 g. ofN-phenyl-6,7-dimethoxy-2-naphthaleneethylamine hydrochloride, m.p.175°-177° C.

EXAMPLE 55

Following a procedure similar to that in Example 52 but using 14.0 g. of6,7-dimethoxy-8-methyl-2-naphthaleneacetamide and 175 ml. of a 1 Msolution of borane in tetrahydrofuran, yielded 13.0 g. of6,7-dimethoxy-8-methyl-2-naphthaleneethylamine hydrochloride, m.p.205°-215° C.

EXAMPLE 56

Following a procedure similar to that in Example 52 but using 10.0 g. of6,7-diethoxy-2-naphthaleneacetamide and 115 ml. of a 1 M solution ofborane in tetrahydrofuran, and isolating the product in the free-baseform yielded 2.3 g. of 6,7-diethoxy-2-naphthaleneethylamine, m.p.109°-111° C. (benzene-n-hexane).

EXAMPLE 57

Following a procedure similar to that in Example 56 but using 10.0 g. of1-(6,7-diethoxy-2-naphthylacetyl)pyrrolidine and 97 ml. of a 1 Msolution of borane in tetrahydrofuran afforded 7.0 g. of1-[2-(6,7-diethoxy-2-naphthyl)ethyl]pyrrolidine, m.p. 71°-74° C.

EXAMPLE 58

A mixture of 13.0 g. ofβ-chloro-6,7-dimethoxy-α-methyl-2-naphthaleneethylamine hydrochloride,1.5 g. of 10% palladium-on-carbon and 200 ml. of dimethylformamide wasshaken under a hydrogen pressure of 20-50 psi for six hours. Thecatalyst was removed by filtration and the filtrate was evaporated invacuo. The residue was recrystallized from 2-propanol to give 8.8 g. of6,7-dimethoxy-α-methyl-2-naphthaleneethylamine hydrochloride, m.p.226°-228° C.

EXAMPLE 59

To a stirred suspension of 0.5 g. of lithium aluminum hydride in 25 ml.of tetrahydrofuran at room temperature was added 1.0 g. of6,7-dimethoxy-α,α-dimethyl-2-naphthaleneacetonitrile. The mixture washeated under reflux two hours, cooled and treated with 1 ml. of waterand 3 ml. of 2 N aqueous sodium hydroxide, stirred one hour at roomtemperature then filtered. The filtrate was evaporated to dryness invacuo and the residue was dissolved in ethyl acetate, washed with water,dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.Recrystallization of the residue from aqueous methanol yielded 0.88 g.of 6,7-dimethoxy-β,β-dimethyl-2-naphthaleneethylamine, m.p. 66°-68° C.(resolidifies and melts at 105° C.).

This compound showed significant antihypertensive activity whenadministered orally at three dose levels of 12.5, 25 and 50 mg./kg. toadrenal regeneration hypertensive rats prepared according to the methodsdescribed by F. R. Shelton et al., Archives of Internal Medicine 98, 449(1956) and Circulation Research Supplement 1, Vols. 24 and 25, May 1969at pages I-35 through 56.

EXAMPLE 60

A solution containing 7.0 g. of 6,7-dimethoxy-1-naphthaleneacetonitrilein 200 ml. of 6.5 N methanolic ammonia was hydrogenated in the presenceof Raney nickel under a hydrogen pressure of 40 psi at 40° C. forapproximately eight hours. The catalyst was removed by filtration andthe filtrate was evaporated in vacuo. The residue was dissolved indilute hydrochloric acid, and the insoluble solids removed byfiltration. The filtrate was made basic with dilute aqueous sodiumhydroxide and extracted with ethyl acetate. Evaporation of the ethylacetate afforded 6.3 g. of 6,7-dimethoxy-1-naphthaleneethylamine whichwas converted directly to 4.3 g. of 5-(2-aminoethyl)-2,3-naphthalenediolhydrochloride as described hereinabove in Example 13.

EXAMPLE 61

To a stirred mixture containing 2.0 g. of lithium aluminum hydride in100 ml. of tetrahydrofuran was added portionwise 4.4 g. of6,7-dimethoxy-1-naphthamide. The reaction mixture was stirred underreflux one hour, cooled and then treated successively with 2 ml. ofwater and 7 ml. of 2 N aqueous sodium hydroxide. The solids were removedby filtration and the filtrate evaporated to dryness in vacuo. Theresidue was recrystallized from benzene-n-hexane to give 3.4 g. of6,7-dimethoxy-1-naphthalenemethylamine, m.p. 116°-118° C.

EXAMPLE 62

Following a procedure similar to that in Example 61 but using 14.0 g. of6,7-dimethoxy-2-naphthamide and 4.0 g. of lithium aluminum hydride,there was obtained 11.0 g. of 6,7-dimethoxy-2-naphthalenemethylamine,m.p. 100°-104° C.

EXAMPLE 63

Following a procedure similar to that in Example 61 but using 31.1 g. ofN-ethyl-6,7-dimethoxy-2-naphthamide and 4.6 g. of lithium aluminumhydride provided the amine which was dissolved in ethyl acetate, washedwith water and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and evaporated to dryness. The residue was dissolvedin ethanol and acidified with methanolic hydrogen chloride. Addition ofether precipitated the salt. Two recrystallizations from 2-propanolafforded 9.8 g. of N-ethyl-6,7-dimethoxy-2-naphthalenemethylaminehydrochloride, m.p. 198°-206° C.

EXAMPLE 64

Following a procedure similar to that in Example 63 but using 33.0 g.N,N-diethyl-6,7-dimethoxy-2-naphthamide and 3.4 g. of lithium aluminumhydride, there was obtained 25.8 g. ofN,N-diethyl-6,7-dimethoxy-2-naphthalenemethylamine hydrochloride, m.p.201°-203° C.

EXAMPLE 65

Following a procedure similar to that in Example 63 but using 37.2 g. of1-(6,7-dimethoxy-2-naphthoyl)pyrrolidine and 4.9 g. of lithium aluminumhydride yielded 15.7 g. of1-[(6,7-dimethoxy-2-naphthyl)methyl]pyrrolidine hydrochloride, m.p.225°-228° C.

EXAMPLE 66

A solution containing 20.0 g. of2-bromo-6',7'-dimethoxy-2'-acetonaphthone in 350 ml. of acetonitrile wasadded over one hour to a stirred solution of 80 ml. of tertbutylamine in500 ml. of acetonitrile at -20° C. When the addition was complete themixture was stirred an additional fifteen minutes at -20° C., thenquenched in water and extracted with ether. The ethereal extracts weredried over anhydrous sodium sulfate and acidified with methanolichydrogen chloride. The product was collected and recrystallized frommethanol-ether to give 17.0 g. of2-(tert-butylamino)-6',7'-dimethoxy-2'-acetonaphthone hydrochloride,m.p. >265° C. (dec.).

EXAMPLE 67

Following a procedure similar to that in Example 66 but using 20.0 g. of2-bromo-6',7'-dimethoxy-1'-acetonaphthone and 80 ml. of tert-butylamine,there was obtained 8.5 g. of2-(tert-butylamino)-6',7'-dimethoxy-1'-acetonaphthone hydrochloride,m.p. 230°-235° C.

EXAMPLE 68

Following a procedure similar to that in Example 66 but using 30.9 g. of2-bromo-6',7'-dimethoxy-2'-acetonaphthone and 25 g. of benzylmethylaminethere was obtained 38.5 g. of2-(benzylmethylamino)-6',7'-dimethoxy-2'-acetonaphthone hydrochloridewhich was used immediately to prepare6,7-dihydroxy-α-[(methylamino)methyl]-2-naphthalenemethanol as describedin Example 26.

EXAMPLE 69

Following a procedure similar to that in Example 66 but using 23.0 g. of2-bromo-6',7'-dimethoxy-2'-acetonaphthone and 29.5 g. of dibenzylamineafforded 26 g. of 2-(dibenzylamino)-6',7'-dimethoxy-2'-acetonaphthonehydrochloride, m.p. 185° C.

EXAMPLE 70

Following a procedure similar to that in Example 66 but using 20.0 g. of2-bromo-6',7'-dimethoxy-2'-acetonaphthone and 60 ml. of 40% aqueousdimethylamine yielded 14.1 g. of2-(dimethylamino)-6',7'-dimethoxy-2'-acetonaphthone hydrochloride, m.p.236°-237° C. (dec.).

A 6.5-gram sample of this material, and 1.0 g. of 10%palladium-on-carbon in 100 ml. of dimethylformamide was shaken fourhours under a hydrogen pressure of 30-50 psi. The catalyst was removedby filtration and the filtrate evaporated to dryness in vacuo.Recrystallization from methanol-ether yielded 5.4 g. of6,7-dimethoxy-α-[(dimethylamino)methyl]-2-naphthalenemethanolhydrochloride, m.p. 219°-220° C. (dec.).

EXAMPLE 71

Following a procedure similar to that in Example 66 but using 50.0 g. of2-bromo-6',7'-dimethoxy-2'-acetonaphthone and 50 ml. of pyrrolidinethere was obtained 27 g. of6',7'-dimethoxy-2-(1-pyrrolidino)-2'-acetonaphthone hydrochloride, m.p.204°-206° C.

Catalytic reduction of a 7.8-gram sample of the above product accordingto a method similar to that in Example 70 provided 6.4 g. of6,7-dimethoxy-α-[(1-pyrrolidinyl)methyl]-2-naphthalenemethanolhydrochloride, m.p. 224°-225° C. (dec.).

EXAMPLE 72

A solution containing 2.17 g. of diethyl acetamidomalonate in 25 ml. ofdimethyl sulfoxide was added dropwise over fifteen minutes to a stirredmixture of 0.42 g. of a 57% mineral oil dispersion of sodium hydride in20 ml. of dimethylsulfoxide. After stirring twenty minutes at roomtemperature, a solution containing 2.36 g. of6-(chloromethyl)-2,3-dimethoxynaphthalene in 20 ml. of dimethylsulfoxidewas added dropwise over ten minutes. The resulting mixture was stirredovernight at room temperature then poured into water and extractedthoroughly with chloroform. The organic extracts were washedsuccessively with water and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate and evaporated to dryness. The residue wasfirst triturated with n-hexane and finally recrystallized frombenzene-ether-n-hexane to give 2.0 g. of diethyl2-acetamido-2-(6,7-dimethoxy-2-naphthylmethyl)malonate, m.p. 130°-137°C.

EXAMPLE 73

A solution containing 4.39 g. of 6,8-dimethoxy-1-naphthaleneacetonitrilein 100 ml. of 5.6 N methanolic ammonia was shaken under a hydrogenpressure of 50 psi in the presence of Raney nickel until two molarequivalents of hydrogen were absorbed. The catalyst was removed byfiltration and the filtrate was evaporated to dryness in vacuo. Theresidue was dissolved in toluene and the solution evaporated to drynessin vacuo and the process was repeated a second time. The residue wasdissolved in a mixture of 10 ml. of ethanol and 50 ml. of toluene andtreated with 3 ml. of 6 N ethanolic hydrogen chloride to give 4.15 g. of6,8-dimethoxy-1-naphthaleneethylamine hydrochloride, m.p. 238° C.(dec.).

EXAMPLE 74

A solution containing 18.0 g. of1,5-dimethoxy-4-(2-nitrovinyl)naphthalene in 150 ml. of tetrahydrofuranwas added dropwise to a stirred suspension of 9.0 g. of lithium aluminumhydride in 100 ml. of tetrahydrofuran. When the addition was complete,the mixture was heated under reflux for six hours, then cooled andtreated successively with 50 ml. of water, 10 ml of 20% aqueous sodiumhydroxide, 30 ml. of water and 170 ml. of dichloromethane. Afterstirring one hour the mixture was filtered and the filtrate evaporatedin vacuo. The residue was dissolved in chloroform, dried over anhydroussodium sulfate and evaporated to dryness. The residue was dissolved inmethanol and acidified with methanolic hydrogen chloride. Evaporation todryness left the crude salt which was partitioned between chloroform anddilute aqueous sodium hydroxide. The chloroform extracts were processedas above and the salt so obtained was repeatedly recrystallized frommethanol-ether to give 7.3 g. of 4,8-dimethoxy-1-naphthaleneethylaminehydrochloride, m.p. 301°-305° C. (dec.).

EXAMPLE 75

A mixture containing 16.0 g. ofα-[(dimethylamino)methyl]-4,8-dimethoxy-1-naphthalenemethanolhydrochloride, 2.0 g. of 10% palladium-on-carbon, 160 ml. of aceticacid, 20 ml. of water and 20 ml. of concentrated hydrochloric acid wasshaken nine hours under a hydrogen pressure of 20-50 psi at roomtemperature. The catalyst was removed by filtration and the filtrate wasevaporated to dryness in vacuo. The residue was dissolved in diluteaqueous hydrochloric acid, washed with ether and made alkaline with 10%aqueous potassium carbonate. The precipitated solid was collected,dissolved in chloroform, the solution dried over anhydrous magensiumsulfate and evaporated to dryness. The residue was dissolved in etherand acidified with methanolic hydrogen chloride. Evaporation to drynessand recrystallization of the residue from absolute ethanol-etherafforded 8.5 g. of N,N-diethyl-4,8-dimethoxy-1-naphthaleneethylaminehydrochloride, m.p. 198°-199° C. (dec.).

EXAMPLE 76

Following a procedure similar to that described in Example 75 but using18.0 g. of4,8-dimethoxy-α-[(1-pyrrolidinyl)methyl]-1-naphthalenemethanolhydrochloride, there was obtained 12.4 g. of1-[2-(4,8-dimethoxyl-1-naphthyl)ethyl]pyrrolidine hydrochloride, m.p.264°-265° C. (dec.).

EXAMPLE 77

A suspension of 13.3 g. of2-(tert-butylamino)-4',8'-dimethoxy-1'-acetonaphthone in 800 ml. oftetrahydrofuran was added over 1.5 hours to a stirred suspension of 6.0g. of lithium aluminum hydride in 200 ml. of tetrahydrofuran. When theaddition was complete the reaction mixture was heated under refluxseventeen hours. The mixture was cooled, treated successively with 35ml. of water, 25 ml. of 20% aqueous sodium hydroxide and 50 ml. ofwater, stirred one hour, diluted with 150 ml. of dichloromethane andfiltered. The filtrate was evaporated to dryness in vacuo. The residuewas triturated with ether and collected. The product was dissolved inmethanol, acidified with methanolic hydrogen chloride and diluted withether. The product was collected and recrystallized from methanol-etherto give 2.2 g. ofα-[(tert-butylamino)methyl]-4,8-dimethoxy-1-naphthalenemethanolhydrochloride, m.p. 256°-257° C. (dec.).

EXAMPLE 78

Following a procedure similar to that described in Example 77 but using22.0 g. of 2-(dimethylamino)-4',8'-dimethoxy-1'-acetonaphthone and 8.0g. of lithium aluminum hydride, there was obtained 18.3 g. ofα-[(diethylamino)-methyl]-4,8-dimethoxy-1naphthalenemethanolhydrochloride, m.p. 183°-184° C. (dec.).

EXAMPLE 79

Following a procedure similar to that described in Example 77 but using13.0 g. of 4',8'-dimethoxy-2-(1-pyrrolidinyl)-1'-acetonaphthone and 3.8g. of lithium aluminum hydride yielded 6.7 g. of4,8-dimethoxy-α-[(1-pyrrolidinyl)methyl]-1-naphthalenemethanolhydrochloride m.p. 211°-212° C. (dec.).

EXAMPLE 80

A solution containing 26.5 g. of2-chloro-4',8'-dimethoxy-1'-acetonaphthone in 150 ml. of acetonitrilewas added dropwise to a stirred solution of 30 ml. of pyrrolidine in 200ml. of acetonitrile. When the addition was complete the mixture washeated under reflux seventeen hours. The solvents were evaporated invacuo and the residue was partitioned between dilute aqueous potassiumcarbonate and ether-ethyl acetate. The organic extracts were evaporatedto dryness and the residue was dissolved in ether and extracted withdilute hydrochloric acid. The acidic extracts were made alkaline with 2N aqueous sodium hydroxide and extracted with chloroform. The chloroformextracts were dried over anhydrous sodium sulfate and evaporated todryness. The residue was dissolved in methanol, acidified withmethanolic hydrogen chloride and diluted with ether. The product wascollected and recrystallized twice from methanol-ether to give 24.0 g.of 4',8'-dimethoxy-2-(1-pyrrolidinyl)-1'-acetonaphthone hydrochloride,m.p. 227°-228° C. (dec.).

EXAMPLE 81

Following a procedure similar to that described in Example 80 but using30.0 g. 2-chloro-4',8'-dimethoxy-1'-acetonaphthone and 150 ml. ofdiethylamine and isolating the product as the free base provided 25.5 g.of 2-(diethylamino)-4',8'-dimethoxy-1'-acetonaphthone, m.p. 84°-85° C.(dec.).

A 2.5-gram sample of the base was converted to its salt as in Example 80giving 2.1 g. of 2-(diethylamino)-4',8'-dimethoxy-1'-acetonaphthonehydrochloride, m.p. 200°-202° C. (dec.).

EXAMPLE 82

Following a procedure similar to that described in Example 80 but using100 ml. of tert-butylamine and 2-iodo-4',8'-dimethoxy-1'-acetonaphthoneobtained by reacting 24.7 g. of2-chloro-4',8'-dimethoxy-1'-acetonaphthone with 15.0g. of sodium iodidein 400 ml. of refluxing acetone, there was obtained 17.0 g. of2-(tert-butylamino)-4',8'-dimethoxy-1'-acetonaphthone, m.p. 107°-110° C.

A 2.2-gram sample of the base was converted to its salt as in Example 80giving 2.1 g. of 2-(tert-butylamino)-4',8'-dimethoxy-1'-acetonaphthonehydrochloride, m.p. 233°-235° C. (dec.).

EXAMPLE 83

A mixture containing 17.9 g. of 6-methoxy-2-naphthaleneacetamide, 250ml. of a 1 M solution of borane in tetrahydrofuran, and 350 ml. oftetrahydrofuran was heated under reflux for 36 hours. The mixture wascooled and treated dropwise with 30 ml. of methanol followed by 70 ml.of 4 N methanolic hydrogen chloride. The resulting mixture was stirredone hour at 0°-5° C., then ten hours at room temperature and finally onehour at the reflux temperature. Evaporation to dryness followed byrecrystallization from methanol-ether afforded 11.5 g. of6-methoxy-2-naphthaleneethylamine hydrochloride, m.p. 306°-308° C.

EXAMPLE 84

Following a procedure similar to that described in Example 83 but using2.9 g. of N-ethyl-6-methoxy-2-naphthaleneacetamide and 36 ml. of a 1 Msolution of borane in tetrahydrofuran, there was obtained 2.5 g. ofN-ethyl-6-methoxy-2-naphthaleneethylamine hydrochloride, m.p.247.5°-248° C.

EXAMPLE 85

A solution containing 5.8 g. of1-(6-methoxy-2-naphthylacetyl)pyrrolidine in 125 ml. of tetrahydrofuranwas added dropwise to a stirred, refluxing mixture of 1.7 g. of lithiumaluminum hydride in 100 ml. of tetrahydrofuran. When addition wascomplete reflux was continued one hour. The cooled reaction mixture wastreated successively with 8.5 ml. of water, 1.7 ml. of 20% aqueoussodium hydroxide, 5.5 ml. of water and 125 ml. of dichloromethane. Themixture was filtered and the filtrate evaporated to dryness. The residuewas dissolved in chloroform, washed with water, dried over anhydrouspotassium carbonate and evaporated to dryness. The residue was dissolvedin ether and acidified with methanolic hydrogen chloride. Theprecipitated product was collected and recrystallized frommethanol-ether to give 4.4 g. of1-[2-(6-methoxy-2-naphthyl)ethyl]pyrrolidine hydrochloride, m.p.230°-230.5° C.

EXAMPLE 86

Following a procedure similar to that described in Example 85 but using4.0 g. of 1-[2-(6-methoxy-2-naphthyl)propionyl]pyrrolidine and 1.1 g. oflithium aluminum hydride, there was obtained 2.9 g. of1-[2-(6-methoxy-2-naphthyl)propyl]-pyrrolidine hydrochloride, m.p.185.5°-186° C.

EXAMPLE 87

A mixture of 6.6 g. of 7-methoxy-2-naphthaleneacetonitrile, one teaspoonof Raney nickel, 7.5 ml. of liquid ammonia and 75 ml. of methanol wasshaken under a hydrogen pressure of 1030 psi at room temperature 48hours and then at 50° C. eight hours. The solvents were evaporated andthe residue distilled under vacuum to give 4.2 g. of base (b.p. 105°C./0.05 mm.) which was dissolved in methanol, acidified with methanolichydrogen chloride and diluted with ether to give 4.0 g. of7-methoxy-2-naphthaleneethylamine hydrochloride, m.p. 265° C.

EXAMPLE 88

Following a procedure similar to that described in Example 83 but using8.5 g. of 2-(6-methoxy-2-naphthyl)propionamide and 111 ml. of a 1 Msolution of borane in tetrahydrofuran, there was obtained 6.7 g. of6-methoxy-α-methyl-2-naphthaleneethylamine hydrochloride, m.p. 197°-198°C.

EXAMPLE 89

To a solution containing 10.8 g. of6,7-dimethoxy-2-naphthaleneethylamine hydrochloride and 7.1 g. ofbenzylacetone in 260 ml. of warm methanol, adjusted to pH 6.0 withmethanolic potassium hydroxide there was added 4.0 g. of 3 A molecularsieve and a solution of 3.3 g. of sodium cyanoborohydride in 60 ml. ofmethanol. The reaction mixture was stirred at room temperature 72 hourswhile maintaining a pH of 5.5-6.5 by periodic addition of acetic acid.The reaction mixture was filtered, the filtrate acidified to pH 2 andevaporated. The residue was dissolved in 300 ml. of boiling methanol,filtered, the filtrate made strongly alkaline with 35% aqueous sodiumhydroxide and decanted from the precipitated solids. The solids werewashed with chloroform and the washings were combined with the methanolsupernatant and filtered. The filtrate was evaporated to dryness. Theresidue was dissolved in ether and acidified with 6 N methanolichydrogen chloride. The product was collected and recrystallized frommethanol-ether to give 5.7 g. ofN-(1-methyl-3-phenylpropyl)-6,7-dimethoxy-2-naphthaleneethylaminehydrochloride, m.p. 188°-190° C.

EXAMPLE 90

Following a procedure similar to that described in Example 89 but using5.4 g. of 6,7-dimethoxy-2-naphthaleneethylamine hydrochloride, 4.0 g. ofp-methoxybenzylacetone and 1.7 g. of sodium cyanoborohydride, there wasobtained 3.7 g. ofN-[3-(p-methoxyphenyl)-1-methylpropyl]-6,7-dimethoxy-2-naphthaleneethylaminehydrochloride, m.p. 190°-191° C.

EXAMPLE 91

To a stirred suspension of 13.2 g. ofα-(1-aminoethyl)-6,7-dimethoxy-2-naphthalenemethanol in 125 ml. ofchloroform was added dropwise 10 ml. of thionyl chloride. When theaddition was complete the mixture was heated under reflux one hour, andthen evaporated to dryness in vacuo. The residue was dissolved in 100ml. of acetone and dry hydrogen chloride was passed into the solution toprecipitate the product. There was obtained 12.2 g. ofβ-chloro-6,7-dimethoxy-α-methyl-2-naphthaleneethylamine hydrochloride,m.p. 190°-192° C. (dec.).

EXAMPLE 92

A solution containing 40.0 g. of crude 6,7-dimethoxy-2-naphthaleneacetylchloride in 500 ml. of ether was added over 0.5 hours to one liter ofstirred 20% aqueous methylamine at 0° C. The resulting mixture wasallowed to stand until the ether had evaporated. The product wascollected and recrystallized from aqueous methanol to give 17.5 g. ofN-methyl-6,7-dimethoxy-2-naphthaleneacetamide, m.p. 167°-169° C.

EXAMPLE 93

Following a procedure similar to that described in Example 92 but using44 g. of 6,7-dimethoxy-2-naphthaleneacetyl chloride in 500 ml. of anether-tetrahydrofuran mixture and one liter of 20% aqueous ethylamine,afforded 26.0 g. of N-ethyl-6,7-dimethoxy-2-naphthaleneacetamide, m.p.152°-154° C.

EXAMPLE 94

Following a procedure similar to that described in Example 92 but using12.0 g. of 6,7-dimethoxy-2-naphthaleneacetyl chloride and 20.0 g. ofpiperidine, there was obtained 8.3 g. of1-(6,7-dimethoxy-2-naphthylacetyl)piperidine, m.p. 85°-87° C.

EXAMPLE 95

Following a procedure similar to that described in Example 92 but using12.0 g. of 6,7-dimethoxy-2-naphthaleneacetyl chloride and 20.0 g. ofmorpholine yielded 9.3 g. of4-(6,7-dimethoxy-2-naphthylacetyl)morpholine, m.p. 137°-139° C.

EXAMPLE 96

Following a procedure similar to that described in Example 92 but using40 g. of 6,7-dimethoxy-2-naphthaleneacetyl chloride and 1 liter of 20%aqueous diethylamine, there was obtained 38 g. ofN,N-diethyl-6,7-dimethoxy-2-naphthaleneacetamide, m.p. 69°-71° C.

EXAMPLE 97

To a stirred solution containing the crude acid chloride obtained from60.0 g. of 6,7-dimethoxy-2-naphthaleneacetic acid in ether, there wasadded dropwise 60 ml. of pyrrolidine. After standing overnight thereaction mixture was partitioned between ethyl acetate and water; theorganic layer was washed successively with dilute hydrochloric acid,water, and saturated aqueous sodium chloride, dried over anhydroussodium sulfate, and evaporated to dryness in vacuo. Recrystallization ofthe residue from benzene-n-hexane afforded 54.0 g. of1-(6,7-dimethoxy-2-naphthylacetyl)pyrrolidine, m.p. 100°-101° C.

EXAMPLE 98

To the crude acid chloride prepared from 24.0 g.6,7-dimethoxy-8-methyl-2-naphthaleneacetic acid was added with swirling450 ml. of cold concentrated aqueous ammonia. After standing at roomtemperature three hours, the product was collected and recrystallizedfrom ethyl acetate to give 15.0 g. of6,7-dimethoxy-8-methyl-2-naphthaleneacetamide, m.p. 180°-183° C.

EXAMPLE 99

To 300 ml. of stirred concentrated aqueous ammonia was added 15.0 g. of6,7-diethoxy-2-naphthaleneacetyl chloride. The mixture was stirred fivehours. The solid product was dissolved in ethyl acetate, washedsuccessively with water, dilute hydrochloric acid, aqueous sodiumbicarbonate, and saturated aqueous sodium chloride, dried over anhydroussodium sulfate and evaporated to dryness. Recrystallization of theresidue from methanol afforded 11.0 g. of6,7-diethoxy-2-naphthaleneacetamide, m.p. 154°-156° C.

EXAMPLE 100

Following a procedure similar to that described in Example 99 but using15.0 g. of 6,7-diethoxy-2-naphthaleneacetyl chloride and 40 ml. ofpyrrolidine, there was obtained 11.0 g. of1-(6,7-diethoxy-2-naphthylacetyl)pyrrolidine, m.p. 93°-95° C.

EXAMPLE 101

A solution containing 19.0 g. of aniline in 150 ml. of benzene was addeddropwise to a stirred solution of 15.0 g. of6,7-dimethoxy-2-naphthaleneacetyl chloride in 300 ml. of benzene. Whenthe reaction was complete the mixture was washed with 10% hydrochloricacid, 10% aqueous sodium hydroxide, water, and finally saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and evaporatedto dryness. The residue was recrystallized from chloroform-n-hexane togive 9.5 g. of 6,7-dimethoxy-N-phenyl-2-naphthaleneacetamide, m.p.140°-141° C.

EXAMPLE 102

Following a procedure similar to that described in Example 99 but using525 ml. of 35% aqueous hexamethyleneimine and 30 g. of6,7-dimethoxy-2-naphthaleneacetyl chloride, there was obtained 17.1 g.of 1-(6,7-dimethoxy-2-naphthylacetyl)hexamethyleneimine, m.p. 51°-62° C.

EXAMPLE 103

To a solution containing 3.6 ml. of 2-methylpiperidine in 300 ml. oftetrahydrofuran was added dropwise a solution of the crude acidchloride, obtained from 25.0 g. of 6,7-dimethoxy-2-naphthaleneaceticacid, in 500 ml. of tetrahydrofuran. The mixture was stirred two hoursat room temperature and then evaporated to dryness in vacuo. The residuewas dissolved in ether, washed successively with water, 2 N hydrochloricacid, saturated aqueous sodium bicarbonate and water, dried overanhydrous magnesium sulfate and evaporated leaving 33.9 g. of1-(6,7-dimethoxy-2-naphthylacetyl)-2-methylpiperidine which wassubsequently converted to1-[2-(6,7-dimethoxy-2-naphthyl)ethyl]-2-methylpiperidine hydrochlorideas described hereinabove in Example 51.

EXAMPLE 104

A solution containing 62.4 g. of bromine in 500 ml. of chloroform wasadded dropwise to a stirred solution of 90.0 g. of6',7'-dimethoxy-2'-acetonaphthone at room temperature. When the additionwas complete the chloroform solution was washed successively with water,saturated aqueous sodium bicarbonate and water, dried over anhydrousmagnesium sulfate and evaporated to dryness in vacuo. Trituration withn-hexane afforded 73.0 g. of 2-bromo-6',7'-dimethoxy-2'-acetonaphthone,m.p. 135°-136° C.

EXAMPLE 105

Following a procedure similar to that described in Example 104 but using2.3 g. of 6',7'-dimethoxy-1'-acetonaphthone and 1.6 g. of bromine, therewas obtained 2.2 g. of 2-bromo-6',7'-dimethoxy-1'-acetonaphthone, m.p.115°-117° C.

EXAMPLE 106

To a stirred solution of 50.0 g. of p-toluenesulfonyl chloride in 350ml. of pyridine at 0° C. there was added 26.0 g. of2-(6,7-dimethoxy-2-naphthyl)ethanol. The mixture was stirred seven hoursat room temperature, and then poured over ice. The product was extractedwith ethyl acetate, washed successively with water, dilute hydrochloricacid and saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was triturated with etherand filtered to give 14.0 g. of 2-(6,7-dimethoxy-2-naphthyl)ethylp-toluenesulfonate, m.p. 103°-104° C. The filtrate was evaporated todryness and the residue crystallized from methanol giving 7.0 g. of6-(2-chloroethyl)-2,3-dimethoxynaphthalene which was converted directlyto N,N-diethyl-6,7-dimethoxy-2-naphthaleneethylamine hydrochloride asdescribed hereinabove in Example 47.

EXAMPLE 107

A solution containing 2.27g. of 6,7-dimethoxy-2-naphthaleneacetonitrileand 2 ml. of methyl iodide in 25 ml. of dimethylformamide was added overten minutes to a mixture of 1.0 g. of a 57% mineral oil dispersion ofsodium hydride in 25 ml. of dimethylformamide. When the addition wascomplete the mixture was stirred two hours at room temperature and then0.5 hours on the steam bath. After cooling, the reaction mixture wasquenched in water and the product collected and recrystallized fromaqueous methanol to give 2.2 g. of6,7-dimethoxy-α,α-dimethyl-2-naphthaleneacetonitrile, m.p. 126°-127° C.

EXAMPLE 108

To a stirred mixture of 12.0 g. of powdered sodium cyanide in 140 ml. ofdimethyl sulfoxide was added portionwise over 10 minutes 20.0 g. of5-chloromethyl-2,3-dimethoxynaphthalene. When the addition was completestirring was continued for an additional 0.5 hours. The reaction waspoured into a large volume of water and extracted with ethyl acetate.The organic extracts were washed with water and saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate and evaporated to dryness.The residue was recrystallized from benzene-n-hexane to give 18.0 g. of6,7-dimethoxy-1-naphthaleneacetonitrile, m.p. 128°-130° C.

EXAMPLE 109

Following a procedure similar to that described in Example 108 but using19.0 g. of 6-chloromethyl-2,3-dimethoxynaphthalene and 10.0 g. of sodiumcyanide there was obtained 7.5 g. of6,7-dimethoxy-2-naphthaleneacetonitrile, m.p. 88°-90° C.

EXAMPLE 110

To 500 ml. of stirred 25% aqueous pyrrolidine at 0° C. was added 35.0 g.of 6,7-dimethoxy-2-naphthoyl chloride. The mixture was stirred at 0° C.ten minutes then at room temperature three hours. The product wascollected and washed with water to give 39.4 g. of1-(6,7-dimethoxy-2-naphthoyl)pyrrolidine, m.p. 123°-126° C.

EXAMPLE 111

Following a procedure similar to that described in Example 110 but using35.0 g. of 6,7-dimethoxy-2-naphthoyl chloride and 500 ml. of 35% aqueousdiethylamine provided 34.7 g. ofN,N-diethyl-6,7-dimethoxy-2-naphthamide, m.p. 108°-110° C.

EXAMPLE 112

Following a procedure similar to that described in Example 110 but using34.0 g. of 6,7-dimethoxy-2-naphthoyl chloride and 500 ml. of 35% aqueousethylamine, there was obtained 32.5 g. ofN-ethyl-6,7-dimethoxy-2-naphthamide, m.p. 164°-166° C.

EXAMPLE 113

Following a procedure similar to that described in Example 98 but usingthe crude acid chloride obtained from 15.0 g. of6,7-dimethoxy-2-naphthoic acid, and 300 ml. of concentrated aqueousammonia, there was obtained 15.0 g. of 6,7-dimethoxy-2-naphthamide, m.p.183°-188° C.

EXAMPLE 114

Following a procedure similar to that described in Example 98 but usingthe crude acid chloride obtained from 0.5 g. of6,7-dimethoxy-1-naphthoic acid, and 30 ml. of concentrated aqueousammonia there was obtained 0.39 g. of 6,7-dimethoxy-1-naphthamide, m.p.187°-189° C.

EXAMPLE 115

A solution containing 29.1 g. of6,8-dimethoxy-1,2,3,4-tetrahydro-1-naphthylideneacetonitrile and 22.8 g.of N-bromosuccinimide in 350 ml. of carbon tetrachloride was heated atreflux three hours under a tungsten-filament flood lamp. The cooledreaction mixture was filtered and the filtrate was washed successivelywith saturated aqueous sodium bicarbonate, 10% aqueous sodium bisulfiteand water, dried over anhydrous sodium sulfate and evaporated todryness. Repeated recrystallization of the residue from carbontetrachloride yielded 3.0 g. of 6,8-dimethoxy-1-naphthaleneacetonitrile,m.p. 106°-109° C.

EXAMPLE 116

A mixture containing 22.0 g. of 4,8-dimethoxy-1-naphthaldehyde, 30 ml.of nitromethane, 15.0 g. of ammonium acetate and 200 ml. of acetic acidwas heated under reflux six hours. The reaction mixture was evaporatedto dryness in vacuo and the residue was partitioned between diluteaqueous sodium bicarbonate and ether. The ethereal solution was washedwith 10% aqueous potassium carbonate and dried over anhydrous magnesiumsulfate. Evaporation of the ether yielded 17.9 g. of1,5-dimethoxy-4-(2-nitrovinyl)naphthalene which was converted directlyto 7.3 g. of 4,8-dimethoxy-1-naphthaleneethylamine hydrochloride asdescribed hereinabove in Example 74.

EXAMPLE 117

To a stirred mixture of 18.0 g. of 1,5-dimethoxynaphthalene and 13.3 g.of aluminum chloride in 300 ml. of dichloromethane at room temperaturewas added dropwise a solution containing 11.4 g. of α-chloroacetylchloride in 50 ml. of dichloromethane. When the addition was complete,stirring at room temperature was continued 48 hours. The mixture wasdiluted with chloroform, washed with dilute hydrochloric acid, driedover anhydrous sodium sulfate, and evaporated to dryness. The residuewas extracted with ether-n-hexane. Evaporation of the extracts andrecrystallization of the residue from ether-n-hexane afforded 14.2 g. of2-chloro-4',8'-dimethoxy-1'-acetonaphthone, m.p. 80°-82° C.

EXAMPLE 118

Following a procedure similar to that described in Example 92 but usingthe crude acid chloride obtained from 4.3 g. of6-methoxy-2-naphthaleneacetic acid, and 60 ml. of 20% aqueous ammonia,there was obtained 2.4 g. of 6-methoxy-2-naphthaleneacetamide, m.p.238°-239° C.

EXAMPLE 119

A solution containing 33 ml. of ethylamine in 330 ml. of ether was addedover 0.5 hours to a stirred solution of 22.0 g. of6-methoxy-2-naphthaleneacetyl chloride in 900 ml. of ether at 0°-5° C.,and stored overnight at 4° C. The precipitated solid was collected andextracted with chloroform. The extracts were washed with water, driedover anhydrous potassium carbonate and evaporated to dryness to give19.0 g. of N-ethyl-6-methoxy-2-naphthaleneacetamide, m.p. 156°-157° C.

EXAMPLE 120

Following a procedure similar to that described in Example 119 but using5.6 g. of 6-methoxy-2-naphthaleneacetyl chloride and 3.6 g. ofpyrrolidine, there was obtained 6.0 g. of1-(6-methoxy-2-naphthylacetyl)pyrrolidine, m.p. 104.5°-105° C.

EXAMPLE 121

Following a procedure similar to that described in Example 119 but using11.0 g. of 2-(6-methoxy-2-naphthyl)propionyl chloride and 7.6 g. ofpyrrolidine, there was obtained 12.4 g. of1-[2-(6-methoxy-2-naphthyl)propionyl]pyrrolidine, which was converteddirectly to 1-[2-(6-methoxy-2-naphthyl)propyl]pyrrolidine hydrochlorideas described hereinabove in Example 86.

EXAMPLE 122

Following a procedure similar to that described in Example 92 but using11.0 g. of 2-(6-methoxy-2-naphthyl)propionyl chloride and 265 ml. of 20%aqueous ammonia, yielded 9.0 g. of 2-(6-methoxy-2-naphthyl)propionamide,m.p. 160° C.

EXAMPLE 123

A solution containing 29.7 g. of3,4-dihydro-7-methoxy-2-naphthaleneacetonitrile in 300 ml. of xylene washeated under reflux 24 hours in the presence of 3.0 g. of 10%palladium-on-carbon. The catalyst was removed by filtration and thefiltrate was evaporated to dryness in vacuo. Trituration of the residuewith chloroform-hexane affored 5.2 g. of7-methoxy-2-naphthaleneacetonitrile, m.p. 84° C.

EXAMPLE 124

A solution containing 18.1 g. of2-dibenzylamino-6'-methoxy-2'-propionaphthone in 200 ml. ofdimethylformamide was shaken at 50° C. overnight in the presence of 2.0g. of 10% palladium-on-carbon under a hydrogen pressure of 40-50 psi.The catalyst was removed by filtration and the filtrate was evaporatedto dryness in vacuo. The residue was dissolved in methanol-ether andacidified with methanolic hydrogen chloride. The product was collectedand recrystallized twice from methanol-ether to give 6.2 g. of6-methoxy-α-(1-aminoethyl)-2-naphthalenemethanol hydrochloride, m.p.247°-248.5° C.

EXAMPLE 125

A mixture containing 41.0 g. of 2-bromo-6'-methoxy-2'-propionaphthoneand 55.2 g. of dibenzylamine in 400 ml. of acetonitrile was stirred atroom temperature 24 hours. The precipitated solid was collected andextracted with chloroform. The chloroform-insoluble material wasseparated and the filtrate was evaporated to dryness. The residue wastriturated with cold ether-n-hexane to give 31.0 g. of2-(dibenzylamino)-6-methoxy-2'-propionaphthone, m.p. 130°-132° C.

EXAMPLE 126

A mixture of 20.5 g. of2-hydroxyimino-6',7'-dimethoxy-2'-propionaphthone, 2 g. of 30%palladium-on-carbon, 31 ml. of concentrated hydrochloric acid andsufficient ethanol to give a total volume of 200 ml. was shaken under ahydrogen pressure of 50 psi at 65° C. approximately five hours. Themixture was diluted with water, the catalyst was removed by filtration,and the filtrate was concentrated. The precipitated product wasdissolved in dilute hydrochloric acid and washed with ether. The aqueousportion was made alkaline with 35% aqueous sodium hydroxide. Theprecipitate was dissolved in chloroform, washed with water and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andevaporated to dryness to give 17.0 g. ofα-(1-aminoethyl)-6,7-dimethoxy-2-naphthalenemethanol, m.p. 165°-172° C.

EXAMPLE 127

To a stirred solution containing 50.0 g. of6,7-dimethoxy-2-naphthaleneacetic acid at 0°-5° C. was added dropwise 40ml. of thionyl chloride. After the addition was complete the reactionmixture was warmed to room temperature and then at 40° C. two hours. Thereaction mixture was evaporated to dryness in vacuo and the residuerecrystallized from ether-n-hexane to give 28 g. of6,7-dimethoxy-2-naphthaleneacetyl chloride, m.p. 56°-62° C.

EXAMPLE 128

A mixture of 24.0 g. of 6,7-dimethoxy-8-methyl-2-naphthaleneacetic acidand 30 ml. of thionyl chloride in 250 ml. of benzene was kept at 40° C.one hour and then overnight at room temperature. The reaction mixturewas then evaporated to dryness in vacuo at 50° C. Additional benzene wasadded and evaporation repeated to give6,7-dimethoxy-8-methyl-2-naphthaleneacetyl chloride. An infraredspectrum indicated no remaining carboxylic acid and this material wasused directly in the preparation of6,7-dimethoxy-8-methyl-2-naphthaleneacetamide as described hereinabovein Example 98.

EXAMPLE 129

Following a procedure similar to that described in Example 128 but using27 g. of 6,7-diethoxy-2-naphthaleneacetic acid, 20 ml. of thionylchloride and one drop of dimethylformamide, there was obtained 31.0 g.of 6,7-diethoxy-2-naphthaleneacetyl chloride which was used directly inthe preparation of 6,7-diethoxy-2-naphthaleneacetamide and1-(6,7-diethoxy-2-naphthylacetyl) pyrrolidine as described hereinabovein Examples 99 and 100, respectively.

EXAMPLE 130

A solution containing 49.2 g. of 6,7-dimethoxy-2-naphthaleneacetic acidin 200 ml. of tetrahydrofuran was added to a stirred solution of 7.6 g.of lithium aluminum hydride in 200 ml. of tetrahydrofuran. When theaddition was complete the mixture was heated under reflux one hour, thencooled and treated with 8 ml. of water followed by 20 ml. of 2 N aqueoussodium hydroxide, and stirred two hours at room temperature. The mixturewas then filtered and the solvent allowed to evaporate over two days.The remaining solid was dissolved in ethyl acetate, washed successivelywith dilute aqueous sodium hydroxide, water, and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and evaporatedto dryness. Recrystallization of the residue from benzene-n-hexaneafforded 29.0 g. of 2-(6,7-dimethoxy-2-naphthyl)ethanol, m.p. 122°-124°C.

EXAMPLE 131

A mixture of 26.0 g. of 6,7-dimethoxy-1-naphthalenemethanol, 60.0 g. ofanhydrous sodium sulfate and 2 liters of benzene was stirred at roomtemperature two hours while hydrogen chloride was bubbled in over twohours. The mixture was filtered and the filtrate evaporated to dryness.The residue was recrystallized from cyclohexane to give 20.0 g. of5-chloromethyl-2,3-dimethoxynaphthalene, m.p. 99°-102° C.

EXAMPLE 132

Following a procedure similar to that described in Example 131 but using29.0 g. of 6,7-dimethoxy-2-naphthalenemethanol and 40 g. of anhydroussodium sulfate there was obtained 24.0 g. of6-chloromethyl-2,3-dimethoxynaphthalene, m.p. 96°-110° C.

EXAMPLE 133

To a solution containing 15.0 g. of 6,7-dimethoxy-2-naphthoic acid andone drop of dimethylformamide in 200 ml. of benzene was added 25 ml. ofthionyl chloride. After heating one hour under reflux the mixture wasevaporated to dryness in vacuo. Additional benzene was added andevaporation repeated to give 6,7-dimethoxy-2-naphthoyl chloride whichwas used directly in the preparation of 6,7-dimethoxy-2-naphthamide asdescribed hereinabove in Example 113.

EXAMPLE 134

Following a procedure similar to that described in Example 133 but using0.5 g. of 6,7-dimethoxy-1-naphthoic acid and 1 ml. of thionyl chloride,there was obtained 6,7-dimethoxy-1-naphthoyl chloride which was useddirectly in the preparation of 6,7-dimethoxy-1-naphthamide as describedhereinabove in Example 114.

EXAMPLE 135

To a stirred mixture of 13.9 g. of a 57% mineral oil dispersion ofsodium hydride in 400 ml. of glyme (freshly distilled from lithiumaluminum hydride) was added dropwise 53 ml. of diethylphosphonoacetonitrile. After 15 minutes a solution containing 60.0 g. of6,8-dimethoxy-1-tetralone in 100 ml. of glyme was added dropwise. Afterstirring overnight at room temperature the mixture was poured into 3liters of ice-water, stirred 0.5 hours and filtered. The product wasrecrystallized from absolute ethanol to give 54.0 g. of1,2,3,4-tetrahydro-6,8-dimethoxy-1-naphthylideneacetonitrile, m.p.101°-102° C.

EXAMPLE 136

Following a procedure similar to that described in Example 108 butsubstituting for 5-chloromethyl-2,3-dimethoxynaphthalene an equivalentamount of 7-chloromethyl-1,3-dimethoxynaphthalene there is obtained6,8-dimethoxy-2-naphthaleneacetonitrile.

EXAMPLE 137

Following a procedure similar to that described in Example 131 butsubstituting for 6,7-dimethoxy-1-naphthalenemethanol an equivalentamount of 6,8-dimethoxy-2-naphthalenemethanol there is obtained7-chloromethyl-1,3-dimethoxynaphthalene.

EXAMPLE 138

To a stirred mixture of 7.1 g. of a 57% mineral oil dispersion of sodiumhydride in 400 ml. of dry glyme under nitrogen was added dropwise 28.0g. of diethyl phosphonoacetonitrile followed by a solution of 25.5 g. of7-methoxy-2-tetralone in 50 ml. of glyme. After stirring four hours atroom temperature the mixture was allowed to stand overnight undernitrogen. The mixture was decanted from an insoluble residue; thesupernatant was concentrated in vacuo, and poured into 350 ml. ofice-water. The product was extracted with chloroform and the extractswere washed with water, dried over anhydrous magnesium sulfate andevaporated to dryness to give 29.9 g of3,4-dihydro-7-methoxy-2-naphthaleneacetonitrile which was converteddirectly to 7-methoxy-2-naphthaleneacetonitrile as described hereinabovein Example 123.

EXAMPLE 139

A suspension of 15.0 g. of2-hydroxyimino-6',7'-dimethoxy-2'-propionaphthone in 500 ml. of absoluteethanol was treated with 25 ml. of 3 N aqueous sodium hydroxide. To theresulting clear solution was added 4.2 g. of sodium borohydride. Afterstirring 2.5 hours at room temperature the mixture was acidified andfiltered. The filtrate was made basic with saturated aqueous sodiumbicarbonate and evaporated to dryness in vacuo. The residue wasextracted with boiling ethyl acetate and isopropyl acetate. The organicextracts were concentrated and cooled to give 7.2 g. of1-(6,7-dimethoxy-2-naphthyl)-1-hydroxy-2-propanone oxime, m.p. 185°-186°C. Concentration of the mother liquors afforded an additional 3.5 g.,m.p. 178°-181° C.

EXAMPLE 140

Hydrogen chloride was bubbled into a refluxing solution containing 23.4g. of 6',7'-dimethoxy-2'-propionaphthone in 200 ml. of benzene and 650ml. of ether while 15 ml. of amyl nitrite was added dropwise to themixture. After standing overnight at room temperature the mixture washeated to reflux while an additional 5 ml. of amyl nitrite was addedover two hours. The mixture was poured on ice and the organic layer waswashed with water and then thoroughly extracted with 10% aqueous sodiumhydroxide. Acidification of the alkaline extracts with 6 N hydrochloricacid precipitated 23.2 g. of2-hydroxyimino-6',7'-dimethoxy-2'-propionaphthone, m.p. 185°-188° C.

EXAMPLE 141

A mixture of 383 g. of 4-(6,7-dimethoxy-2-naphthylthioacetyl)morpholine,250 g. of sodium hydroxide and 800 ml. of water was heated under refluxsix hours. The mixture was evaporated in vacuo and the residue dissolvedin 4 liters of warm water. The aqueous solution was treated withconcentrated hydrochloride acid until a red impurity separated. Thestill-basic solution was cooled and filtered and the filtrate wasacidified with concentrated hydrochloric acid to give 210 g. of6,7-dimethoxy-2-naphthaleneacetic acid, m.p. 140°-143° C.

EXAMPLE 142

A mixture of 4-(6,7-dimethoxy-8-methyl-2-naphthylthioacetyl)morpholineobtained from 41 g. of 6',7'-dimethoxy-8'-methyl-2'-acetonaphthone, 80ml. of ethanol and 200 ml. of 35% aqueous sodium hydroxide was heatedunder reflux one hour. The cooled reaction mixture was diluted with 200ml. of water and washed with chloroform. The aqueous solution wasacidified with dilute hydrochloric acid and the precipitated acid wasdissolved in chloroform, washed with water and saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and evaporated todryness. The residue was recrystallized from benzene-n-hexane to give25.0 g. of 6,7-dimethoxy-8-methyl-2-naphthaleneacetic acid, m.p.115°-120° C.

EXAMPLE 143

A stirred solution containing 35.0 g. of6,7-dihydroxy-2-naphthaleneacetic acid and 50 g. of solid potassiumhydroxide in 350 ml. of water was heated to 85° C. and treatedportionwise with 70 ml. of diethyl sulfate. Another 25 g. of potassiumhydroxide was added followed by 40 ml. of diethyl sulfate. This wasrepeated twice more. The solution was then cooled, filtered andacidified with hydrochloric acid. The precipitated product was dissolvedin chloroform, washed with water, dried over anhydrous magnesium sulfateand evaporated to dryness. The residue was recrystallized fromdiisopropyl ether to give 27.0 g. of 6,7-diethoxy-2-naphthaleneaceticacid, m.p. 117°-120° C.

EXAMPLE 144

To a refluxing solution containing 129.0 g. of6,7-dimethoxy-2-naphthaleneacetic acid in 1 liter of acetic acid, thereis added dropwise, at a rate to maintain a clear solution, 2 liters of48% hydrobromic acid. When the addition was complete reflux wasmaintained for an additional 40 minutes. Cooling the mixture in iceafforded 101.5 g. of 6,7-dihydroxy-2-naphthaleneacetic acid, m.p.218°-222° C.

EXAMPLE 145

Following a procedure similar to that described in Example 130 but using46.4 g. of 6,7-dimethoxy-2-naphthoic acid and 7.6 g. of lithium aluminumhydride there was obtained 29 g. of 6,7-dimethoxy-2-naphthalenemethanol,m.p. 110°-112° C.

EXAMPLE 146

Following a procedure similar to that described in Example 130 but using1.23 g. of 6,7-dimethoxy-1-naphthoic acid and 0.20 g. of lithiumaluminum hydride, there was obtained 0.58 g. of6,7-dimethoxy-1-naphthalenemethanol, m.p. 128°-129° C.

EXAMPLE 147

Following a procedure similar to that described in Example 155 butsubstituting for 1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehydeethylene acetal an equivalent amount of 6,8-dimethoxy-2-naphthaldehyde,there is obtained 6,8-dimethoxy-2-naphthalenemethanol.

EXAMPLE 148

A stirred mixture of 10.3 g. of 6',7'-dimethoxy-2'-acetonaphthone, 2.4g. of sulfur and 6.5 g. of morpholine was slowly heated to 155° C. andmaintained at this temperature ten hours. Trituration with ethanolproduced 12.0 g. of 4-(6,7-dimethoxy-2-naphthylthioacetyl)morpholine,m.p. 155°-165° C. Recrystallization from benzene raised the meltingpoint to 173°-175° C.

EXAMPLE 149

A stirred mixture of 2.0 g. of6',7'-dimethoxy-8'-methyl-2'-acetonaphthone, 0.48 g. of sulfur and 1.3g. of morpholine was heated two hours at 140° C. The mixture was cooledand the residue recrystallized from methanol to give4-(6,7-dimethoxy-8-methyl-2-naphthylthioacetyl)morpholine, m.p.100°-103° C.

EXAMPLE 150

To a stirred solution containing 1 liter of 5.25% aqueous sodiumhypochlorite (Chlorox®) and 80 ml. of 35% aqueous sodium hydroxide at50° C. was added 30 g. of 6',7'-dimethoxy-1'-acetonaphthone. The mixturewas heated at 70°-80° C. for five hours. Five 100 ml. portions ofhypochlorite were added periodically to maintain a positivestarch-iodide test. When all of the solid had dissolved the reactionmixture was cooled, and treated with saturated aqueous sodium bisulfiteuntil a negative starch-iodide test was obtained. The mixture wasfiltered and the filtrate was acidified with concentrated hydrochloricacid to precipitate 26.0 g. of 6,7-dimethoxy-1-naphthoic acid, m.p.230°-234° C.

EXAMPLE 151

A refluxing solution containing 218 mg. of3,4-dihydro-6,8-dimethoxy-2-naphthaldehyde and 196 mg. ofN-bromosuccinimide in 10 ml. of carbon tetrachloride was irradiatedthree hours with a tungsten-filament flood lamp. After irradiation wasstopped, reflux was continued an additional two hours. The cooledmixture was filtered, washed with saturated aqueous sodium bicarbonate,dried over anhydrous sodium sulfate and evaporated to dryness. Theresidue was recrystallized from ethanol to give 50 mg. of6,8-dimethoxy-2-naphthaldehyde, m.p. 165° C.

EXAMPLE 152

To a stirred solution containing 55.0 g. of2,3-dimethoxy-1-methylnaphthalene and 23.0 g. of acetyl chloride in 650ml. of sym-tetrachloroethane at 0° C. was added portionwise 41.0 g. ofaluminum chloride. When the addition was complete the mixture wasstirred three hours at room temperature, diluted with chloroform, andpoured into cold dilute hydrochloric acid. The organic layer was washedwith water, dried over anhydrous sodium sulfate and evaporated todryness. Recrystallization of the residue from benzene-n-hexane afforded42.0 g. of 6',7'-dimethoxy-8'-methyl-2'-acetonaphthone, m.p. 103°-106°C.

EXAMPLE 153

To a stirred solution containing 960 g. of 2,3-dimethoxynaphthalene and430 ml. of acetyl chloride in 6.0 liters of sym-tetrachloroethane at 0°C. was added portionwise 800 g. of aluminum chloride. The mixture wasstirred 3.5 hours at room temperature and then poured into 10 liters ofice-water and 500 ml. of concentrated hydrochloric acid. The layers wereseparated and the aqueous portion extracted with chloroform. Thecombined organic extracts were dried over anhydrous potassium carbonate,concentrated and diluted with 3 liters of methanol. Cooling andfiltering afforded 952 g. of 6',7'-dimethoxy-2'-acetonaphthone. Themother liquors were concentrated and diluted with methanol to give 37.0g. of product which after recrystallization from methanol afforded 26.5g. of 6',7'-dimethoxy-1'-acetonaphthone, m.p. 141°-143° C.Recrystallization of the major product from methanol gave 918 g. of6',7'-dimethoxy-2'-acetonaphthone, m.p. 110°-112° C.

EXAMPLE 154

To a solution containing 4.0 g. of1,2,3,4-tetrahydro-1-hydroxy-6,8-dimethoxy-2-naphthaldehyde ethyleneacetal in 40 ml. of acetic acid was added a solution of 4 ml. ofconcentrated sulfuric acid in 36 ml. of water. The mixture was stirredtwo hours at room temperature and then poured into 200 ml. of water andextracted with ether. The ethereal extracts were washed successivelywith water, saturated aqueous sodium bicarbonate and saturated aqueoussodium chloride, dried over anhydrous sodium sulfate and evaporated todryness. The residue was recrystallized from absolute ethanol to give750 mg. of 3,4-dihydro-6,8-dimethoxy-2-naphthaldehyde, m.p. 100°-102° C.

EXAMPLE 155

A mixture of crude1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehyde ethylene acetalobtained from 5.73 g. of 2-hydroxymethylene-6,8-dimethoxy-1-tetralone,and 0.91 g. of sodium borohydride in 25 ml. of 2-propanol was stirredtwo hours at room temperature. The mixture was cooled and treated with80 ml. of saturated aqueous ammonium chloride and extracted with ether.The ethereal extracts were washed with saturated aqueous solutions ofsodium bicarbonate and sodium chloride, dried over anhydrous magnesiumsulfate and evaporated to dryness to give1,2,3,4-tetrahydro-1-hydroxy-6,8-dimethoxy-2-naphthaldehyde ethyleneacetal which was converted directly to3,4-dihydro-6,8-dimethoxy-2-naphthaldehyde as described hereinabove inExample 154.

EXAMPLE 156

A solution containing 5.73 g. of2-hydroxymethylene-6,8-dimethoxy-1-tetralone, 2.23 g. of ethylene glycoland 100 mg. of p-toluenesulfonic acid in 25 ml. of benzene was heated atreflux two hours under a Dean-Stark water separator. The mixture wasfiltered, the filtrate was washed with saturated aqueous solutions ofsodium bicarbonate and sodium chloride, dried over anhydrous magnesiumsulfate and evaporated to dryness in vacuo to give1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehyde ethylene acetalwhich was converted directly to1,2,3,4-tetrahydro-1-hydroxy-6,8-dimethoxy-2-naphthaldehyde ethyleneacetal as described hereinabove in Example 155.

EXAMPLE 157

To a stirred solution containing 11.6 g. (50.4 mmoles) of2-(6-methoxy-2-naphthyl)propionic acid in 100 ml. of dry tetrahydrofuranwas added in one portion 8.2 g. (50.6 mmoles) of carbonyl diimidazole.After gas evolution had ceased (about 20 minutes) 4.5 g. (51.6 mmoles)of morpholine was added in one portion and the resulting mixture stirredthree hours at room temperature. After standing over the weekend thesolvent was evaporated under vacuum and the residue was dissolved inethyl acetate, washed successively with water, dilute hydrochloric acid,water and saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate and evaporated under vacuum to give 15.5 g. of4-[2-(6-methoxy-2-naphthyl)propionyl]morpholine.

B. To a vigorously stirred mixture containing 15.5 g. (51.8 mmoles) of4-[2-(6-methoxy-2-naphthyl)propionyl]morpholine and 6.7 g. (177 mmoles)of sodium borohydride in 250 ml. of tetrahydrofuran was added dropwiseover three hours a cold solution containing 34.8 g. (0.243 mole) ofboron trifluoride etherate in 50 ml. of tetrahydrofuran. During theaddition, the temperature was maintained below 20° C. When the additionwas complete, the mixture was heated under reflux overnight, then cooledand treated dropwise with 90 ml. of water. The tetrahydrofuran wasboiled off and the residue was acidified with dilute hydrochloric acidand heated on the steam bath overnight. The mixture was then madealkaline with 35% aqueous sodium hydroxide and diluted with ether. Thelayers were separated and the ethereal solution was washed with waterand saturated aqueous sodium chloride and evaporated to dryness. Theresidue was redissolved in ether, filtered and acidified with ethanolichydrogen chloride. The resulting solid was collected, washed with etherand dried at 60° C. under vacuum to give 13.1 g. of4-[2-(6-methoxy-2-naphthyl)propyl]morpholine hydrochloride, m.p.223°-225° C.

We claim:
 1. A compound having the formula ##STR71## wherein the sidechain represented by ##STR72## occupies either position 5 or position 6of the naphthalene nucleus; R and R₁ are independently hydrogen,lower-alkanoyl, benzoyl or benzoyl substituted by from 1 to 2lower-alkyl groups;Q is hydrogen or methyl; A is a direct linkage or CR₅R₆ where R₅ and R₆ are independently hydrogen or methyl; R₂ is hydrogenor methyl, provided that when A is a direct linkage, or when R₅ and/orR₆ are methyl, then R₂ is hydrogen; NR₃ R₄ is pyrrolidino, piperidino,hexamethyleneimino, morpholino or any of these having from one to twoloweralkyl substituents; or an acid-addition salt thereof.
 2. A compoundaccording to claim 1 wherein A is CR₅ R₆.
 3. A compound according toclaim 2 wherein R and R₁ are hydrogen.
 4. A compound according to claim3 wherein Q is hydrogen.
 5. A compound according to claim 4 wherein R₅and R₆ are hydrogen.
 6. A compound according to claim 5 wherein R₂ ishydrogen.
 7. A compound according to claim 6 wherein the side chainrepresented by --CH₂ --CH₂ --NR₃ R₄ occupies position 6 of thenaphthalene nucleus.
 8. 6-[2-(1-Pyrrolidinyl)ethyl]-2,3-naphthalenediolor an acid-addition salt thereof according to claim
 7. 9.6-[2-(2-Methyl-1-piperidinyl)ethyl]-2,3-naphthalenediol or anacid-addition salt thereof according to claim
 7. 10.1-[2-(6,7-Dihydroxy-2-naphthyl)ethyl]piperidine or an acid-addition saltthereof according to claim
 7. 11.6-[2-(1-Hexamethyleneiminyl)ethyl]-2,3-naphthalenediol or anacid-addition salt thereof according to claim
 7. 12. A compoundaccording to claim 1 wherein A is a direct linkage.
 13. A compoundaccording to claim 12 wherein NR₃ R₄ is pyrrolidino, piperidino orhexamethyleneimino.
 14. A compound according to claim 13 wherein R andR₁ are hydrogen.
 15. 6-[(1-Pyrrolidinyl)methyl]-2,3-naphthalenediol oran acid-addition salt thereof according to claim
 14. 16. A compoundhaving the formula ##STR73## wherein the side chain represented by##STR74## occupies either position 7 or position 8 of the naphthalenenucleus; R and R₁ are independently hydrogen, lower alkanoyl, benzoyl orbenzoyl substituted by from 1 to 2 lower-alkyl groups;R₅ and R₆ areindependently hydrogen or methyl; NR₃ R₄ is pyrrolidino, piperidino,hexamethyleneimino, morpholino or any of these having from one to twolower-alkyl substituents; or an acid-addition salt thereof.